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Westerbeke FHM, Rios-Morales M, Attaye I, Nieuwdorp M. Fructose catabolism and its metabolic effects: Exploring host-microbiota interactions and the impact of ethnicity. J Physiol 2025. [PMID: 39805044 DOI: 10.1113/jp287316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Important health disparities are observed in the prevalence of obesity and associated non-communicable diseases (NCDs), including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) among ethnic groups. Yet, the underlying factors accounting for these disparities remain poorly understood. Fructose has been widely proposed as a potential mediator of these NCDs, given that hepatic fructose catabolism can result in deleterious metabolic effects, including insulin resistance and hepatic steatosis. Moreover, the fermentation of fructose by the gut microbiota can produce metabolites such as ethanol and acetate, both which serve as potential substrates for de novo lipogenesis (DNL) and could therefore contribute to the development of these metabolic conditions. Significant inter-ethnic differences in gut microbiota composition have been observed. Moreover, fructose consumption varies across ethnic groups, and fructose intake has been demonstrated to significantly alter gut microbiota composition, which can influence its fermenting properties and metabolic effects. Therefore, ethnic differences in gut microbiota composition, which may be influenced by variations in fructose consumption, could contribute to the observed health disparities. This review provides an overview of the complex interactions between host and microbial fructose catabolism, the role of ethnicity in shaping these metabolic processes and their impact on host health. Understanding these interactions could provide insights into the mechanisms driving ethnic health disparities to improve personalized nutrition strategies. KEY POINTS: Dietary fructose consumption has increased substantially over recent decades, which has been associated with the rising prevalence of obesity and non-communicable diseases (NCDs) such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Pronounced disparities among different ethnic groups in NCD prevalence and dietary fructose consumption underscore the need to elucidate the underlying mechanisms of fructose catabolism and its health effects. Together with the well-known toxic effects of hepatic fructose catabolism, emerging evidence highlights a role for the small intestinal microbiota in fermenting sugars like fructose into various bacterial products with potential deleterious metabolic effects. There are significant ethnic differences in gut microbiota composition that, combined with varying fructose consumption, could mediate the observed health disparities. To comprehensively understand the role of the gut microbiota in mediating fructose-induced adverse metabolic effects, future research should focus on the small intestinal microbiota. Future research on fructose - microbiota - host interactions should account for ethnic differences in dietary habits and microbial composition to elucidate the potential role of the gut microbiota in driving the mentioned health disparities.
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Affiliation(s)
- Florine H M Westerbeke
- Department of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Melany Rios-Morales
- Department of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Ilias Attaye
- Department of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Max Nieuwdorp
- Department of Internal and Experimental Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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Elrashidy RA, Zakaria EM, Hasan RA, Elmaghraby AM, Hassan DA, Abdelgalil RM, Abdelmohsen SR, Negm AM, Khalil AS, Eraque AMS, Ahmed RM, Sabbah WS, Ahmed AA, Ibrahim SE. Implication of endoplasmic reticulum stress and mitochondrial perturbations in remote liver injury after renal ischemia/reperfusion in rats: potential protective role of azilsartan. Redox Rep 2024; 29:2319963. [PMID: 38411133 PMCID: PMC10903753 DOI: 10.1080/13510002.2024.2319963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024] Open
Abstract
Objectives: Distant liver injury is a complication of renal ischemia-reperfusion (I/R) injury, which imposes mortality and economic burden. This study aimed to elucidate the cross-talk of endoplasmic reticulum (ER) stress and mitochondrial perturbations in renal I/R-induced liver injury, and the potential hepatoprotective effect of azilsartan (AZL).Methods: Male albino Wister rats were pre-treated with AZL (3 mg/kg/day, PO) for 7 days then a bilateral renal I/R or sham procedure was performed. Activities of liver enzymes were assessed in plasma. The structure and ultra-structure of hepatocytes were assessed by light and electron microscopy. Markers of ER stress, mitochondrial biogenesis and apoptosis were analyzed in livers of rats.Results: Renal ischemic rats showed higher plasma levels of liver enzymes than sham-operated rats, coupled with histological and ultra-structural alterations in hepatocytes. Mechanistically, there was up-regulation of ER stress markers and suppression of mitochondrial biogenesis-related proteins and enhanced apoptosis in livers of renal ischemic rats. These abnormalities were almost abrogated by AZL pretreatment.Discussion: Our findings uncovered the involvement of mitochondrial perturbations, ER stress and apoptosis in liver injury following renal I/R, and suggested AZL as a preconditioning strategy to ameliorate remote liver injury in patients susceptible to renal I/R after adequate clinical testing.
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Affiliation(s)
- Rania A. Elrashidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Esraa M. Zakaria
- Pharmacology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Rehab A. Hasan
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Asmaa M. Elmaghraby
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Dina A. Hassan
- Histology and Cell Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ranya M. Abdelgalil
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Shaimaa R. Abdelmohsen
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Amira M. Negm
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Azza S. Khalil
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ayat M. S. Eraque
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Reem M. Ahmed
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Walaa S. Sabbah
- Anatomy and Embryology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Ahmed A. Ahmed
- Medical Student, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt
| | - Samah E. Ibrahim
- Medical Physiology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
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Bai Y, Liu Y, Wang Y, Liu X, Wang Y, Liu H, Yi H, Xu C, Zhang F. IL-18BP Therapy Ameliorates Reproductive and Metabolic Phenotypes in a PCOS Mouse Model by Relieving Inflammation, Fibrosis and Endoplasmic Reticulum Stress. Reprod Sci 2024; 31:3595-3608. [PMID: 38977641 DOI: 10.1007/s43032-024-01631-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/22/2024] [Indexed: 07/10/2024]
Abstract
There is a chronic inflammation in PCOS patients, which is correlated with the pathogenesis of PCOS. IL-18 and IL-18BP are related with some inflammatory diseases, while less explored in PCOS. Whether IL-18BP could be a potential drug of PCOS remains unknown.IL-18 and testosterone levels were evaluated in serum of 10 non-PCOS control patients and 20 PCOS patients. Female C57/BL6 mice were gavaged with letrozole to induce PCOS mouse model and IL-18 level was evaluated in the serum of PCOS mouse model, and IL-18 is intraperitoneally injected in female mice, IL-18BP is intraperitoneally injected in the PCOS mice models. Then the body weights, estrous cycles, reproductive hormones and morphology of ovaries were analyzed. The level of ovarian chronic inflammation, fibrosis and endoplasmic reticulum (ER) stress are evaluated.IL-18 levels are increased in the serum of PCOS patients and PCOS mice models respectively. The serum DHEAS, iWAT weight and adipocyte size were increased in IL-18 group compared to the control group (P < 0.05). In the PCOS mouse model treated with IL-18BP, the body weight and serum LH/FSH ratio was decreased compared to the PCOS group (P < 0.05). The expression levels of inflammatory factors and fibrosis-related genes, the expression level of endoplasmic reticulum stress-related genes, and the ROS positive area of ovarian tissue was decreased (P < 0.05).IL-18 is involved in inducing PCOS phenotypes, while IL-18BP relieves PCOS phenotypes by alleviating ovarian chronic inflammation, fibrosis and ER stress in PCOS mice.
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Affiliation(s)
- Yixuan Bai
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Yan Liu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China
| | - Yuhui Wang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Xitong Liu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Yang Wang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China
| | - Haiou Liu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
| | - Huan Yi
- National Key Gynecology Clinical Specialty Construction Unit of China, Fujian Maternity and Child Health Hospital, Fuzhou, China.
| | - Congjian Xu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
- Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China.
| | - Feifei Zhang
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
- Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, China.
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Zhao X, Li Y, Yu J, Teng H, Wu S, Wang Y, Zhou H, Li F. Role of mitochondria in pathogenesis and therapy of renal fibrosis. Metabolism 2024; 155:155913. [PMID: 38609039 DOI: 10.1016/j.metabol.2024.155913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/18/2024] [Accepted: 04/09/2024] [Indexed: 04/14/2024]
Abstract
Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.
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Affiliation(s)
- Xiaodong Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yunkuo Li
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Jinyu Yu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Haolin Teng
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Shouwang Wu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China.
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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6
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Nandwani A, Rathore S, Datta M. LncRNA H19 inhibition impairs endoplasmic reticulum-mitochondria contact in hepatic cells and augments gluconeogenesis by increasing VDAC1 levels. Redox Biol 2024; 69:102989. [PMID: 38100882 PMCID: PMC10761920 DOI: 10.1016/j.redox.2023.102989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/17/2023] [Accepted: 12/06/2023] [Indexed: 12/17/2023] Open
Abstract
Inspite of exerting independent cellular functions, the endoplasmic-reticulum (ER) and the mitochondria also physically connect at specific sites termed mitochondria-associated ER membranes (MAMs) and these sites consist of several tethering proteins that play varied roles in diverse cellular processes. However, the regulation of these tethering proteins within the cell is relatively less studied. Here, we show that several MAM proteins are significantly altered in the liver during diabetes and among these, the lncRNA, H19 regulates the levels of VDAC1. Inhibition of H19 expression using H19 specific siRNA altered VDAC1, mitochondrial Ca2+ and oxygen consumption rate, ATP and ROS levels and enhanced ER and mitochondria coupling in Hepa 1-6 cells. While H19 inhibition did not impact lipid accumulation, levels of gluconeogenic genes were significantly increased. JNK-phosphorylation and IRS1-Ser307-phosphorylation were increased by H19 inhibition and this was associated with abrogation of insulin-stimulated AKT (Ser-473) phosphorylation and glucose uptake in Hepa 1-6 cells. While inhibition of VDAC1 expression using siRNAs and with metformin significantly rescued the effects of H19 inhibition, VDAC1 overexpression alone exerted effects similar to H19 inhibition, suggesting that VDAC1 increase mediates the adverse effects of H19. In-vivo H19 inhibition using specific siRNAs increased hepatic VDAC1, pJNK and pIRS1 (Ser307) levels and decreased AKT (Ser-473) phosphorylation in mice. These suggest an important role of the H19-VDAC1 axis in ER-mitochondria coupling and regulation of gluconeogenesis in the liver during diabetes.
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Affiliation(s)
- Arun Nandwani
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shalu Rathore
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi, 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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7
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Marmolejo-Garza A, Krabbendam IE, Luu MDA, Brouwer F, Trombetta-Lima M, Unal O, O'Connor SJ, Majerníková N, Elzinga CRS, Mammucari C, Schmidt M, Madesh M, Boddeke E, Dolga AM. Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis. Cell Death Dis 2023; 14:772. [PMID: 38007529 PMCID: PMC10676387 DOI: 10.1038/s41419-023-06290-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 10/30/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023]
Abstract
Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.
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Affiliation(s)
- Alejandro Marmolejo-Garza
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Inge E Krabbendam
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Minh Danh Anh Luu
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Famke Brouwer
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Marina Trombetta-Lima
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Osman Unal
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Shane J O'Connor
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Naďa Majerníková
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Carolina R S Elzinga
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Cristina Mammucari
- Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy
| | - Martina Schmidt
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands
| | - Muniswamy Madesh
- Department of Medicine/Cardiology, Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Erik Boddeke
- Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Amalia M Dolga
- Faculty of Science and Engineering, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9713 AV, Groningen, The Netherlands.
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Humbert A, Lefebvre R, Nawrot M, Caussy C, Rieusset J. Calcium signalling in hepatic metabolism: Health and diseases. Cell Calcium 2023; 114:102780. [PMID: 37506596 DOI: 10.1016/j.ceca.2023.102780] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
The flexibility between the wide array of hepatic functions relies on calcium (Ca2+) signalling. Indeed, Ca2+ is implicated in the control of many intracellular functions as well as intercellular communication. Thus, hepatocytes adapt their Ca2+ signalling depending on their nutritional and hormonal environment, leading to opposite cellular functions, such as glucose storage or synthesis. Interestingly, hepatic metabolic diseases, such as obesity, type 2 diabetes and non-alcoholic fatty liver diseases, are associated with impaired Ca2+ signalling. Here, we present the hepatocytes' toolkit for Ca2+ signalling, complete with regulation systems and signalling pathways activated by nutrients and hormones. We further discuss the current knowledge on the molecular mechanisms leading to alterations of Ca2+ signalling in hepatic metabolic diseases, and review the literature on the clinical impact of Ca2+-targeting therapeutics.
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Affiliation(s)
- Alexandre Humbert
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Rémy Lefebvre
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Margaux Nawrot
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France
| | - Cyrielle Caussy
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France; Département Endocrinologie, Diabète et Nutrition, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre-Bénite, France
| | - Jennifer Rieusset
- Laboratoire CarMeN, INSERM U-1060, INRAE U-1397, Université Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France.
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Panico G, Fasciolo G, Migliaccio V, De Matteis R, Lionetti L, Napolitano G, Agnisola C, Venditti P, Lombardi A. 1,3-Butanediol Administration Increases β-Hydroxybutyrate Plasma Levels and Affects Redox Homeostasis, Endoplasmic Reticulum Stress, and Adipokine Production in Rat Gonadal Adipose Tissue. Antioxidants (Basel) 2023; 12:1471. [PMID: 37508009 PMCID: PMC10376816 DOI: 10.3390/antiox12071471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/15/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Ketone bodies (KBs) are an alternative energy source under starvation and play multiple roles as signaling molecules regulating energy and metabolic homeostasis. The mechanism by which KBs influence visceral white adipose tissue physiology is only partially known, and our study aimed to shed light on the effects they exert on such tissue. To this aim, we administered 1,3-butanediol (BD) to rats since it rapidly enhances β-hydroxybutyrate serum levels, and we evaluated the effect it induces within 3 h or after 14 days of treatment. After 14 days of treatment, rats showed a decrease in body weight gain, energy intake, gonadal-WAT (gWAT) weight, and adipocyte size compared to the control. BD exerted a pronounced antioxidant effect and directed redox homeostasis toward reductive stress, already evident within 3 h after its administration. BD lowered tissue ROS levels and oxidative damage to lipids and proteins and enhanced tissue soluble and enzymatic antioxidant capacity as well as nuclear erythroid factor-2 protein levels. BD also reduced specific mitochondrial maximal oxidative capacity and induced endoplasmic reticulum stress as well as interrelated processes, leading to changes in the level of adipokines/cytokines involved in inflammation, macrophage infiltration into gWAT, adipocyte differentiation, and lipolysis.
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Affiliation(s)
- Giuliana Panico
- Department of Biology, University of Naples Federico II, Complesso Monte Sant'Angelo Via Cintia 26, 80126 Napoli, Italy
| | - Gianluca Fasciolo
- Department of Biology, University of Naples Federico II, Complesso Monte Sant'Angelo Via Cintia 26, 80126 Napoli, Italy
| | - Vincenzo Migliaccio
- Department of Chemistry and Biology "A. Zambelli", University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
| | - Rita De Matteis
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Lillà Lionetti
- Department of Chemistry and Biology "A. Zambelli", University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
| | - Gaetana Napolitano
- Department of Science and Technology, Parthenope University of Naples, 80143 Naples, Italy
| | - Claudio Agnisola
- Department of Biology, University of Naples Federico II, Complesso Monte Sant'Angelo Via Cintia 26, 80126 Napoli, Italy
| | - Paola Venditti
- Department of Biology, University of Naples Federico II, Complesso Monte Sant'Angelo Via Cintia 26, 80126 Napoli, Italy
| | - Assunta Lombardi
- Department of Biology, University of Naples Federico II, Complesso Monte Sant'Angelo Via Cintia 26, 80126 Napoli, Italy
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10
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Hogan KA, Zeidler JD, Beasley HK, Alsaadi AI, Alshaheeb AA, Chang YC, Tian H, Hinton AO, McReynolds MR. Using mass spectrometry imaging to visualize age-related subcellular disruption. Front Mol Biosci 2023; 10:906606. [PMID: 36968274 PMCID: PMC10032471 DOI: 10.3389/fmolb.2023.906606] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 01/24/2023] [Indexed: 03/10/2023] Open
Abstract
Metabolic homeostasis balances the production and consumption of energetic molecules to maintain active, healthy cells. Cellular stress, which disrupts metabolism and leads to the loss of cellular homeostasis, is important in age-related diseases. We focus here on the role of organelle dysfunction in age-related diseases, including the roles of energy deficiencies, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, changes in metabolic flux in aging (e.g., Ca2+ and nicotinamide adenine dinucleotide), and alterations in the endoplasmic reticulum-mitochondria contact sites that regulate the trafficking of metabolites. Tools for single-cell resolution of metabolite pools and metabolic flux in animal models of aging and age-related diseases are urgently needed. High-resolution mass spectrometry imaging (MSI) provides a revolutionary approach for capturing the metabolic states of individual cells and cellular interactions without the dissociation of tissues. mass spectrometry imaging can be a powerful tool to elucidate the role of stress-induced cellular dysfunction in aging.
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Affiliation(s)
- Kelly A. Hogan
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States
- Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, United States
- Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States
| | - Julianna D. Zeidler
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Heather K. Beasley
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
| | - Abrar I. Alsaadi
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States
| | - Abdulkareem A. Alshaheeb
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States
| | - Yi-Chin Chang
- Department of Chemistry, Pennsylvania State University, University Park, PA, United States
| | - Hua Tian
- Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States
- Department of Chemistry, Pennsylvania State University, University Park, PA, United States
- *Correspondence: Hua Tian, ; Antentor O. Hinton Jr, ; Melanie R. McReynolds,
| | - Antentor O. Hinton
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, United States
- *Correspondence: Hua Tian, ; Antentor O. Hinton Jr, ; Melanie R. McReynolds,
| | - Melanie R. McReynolds
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States
- Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, United States
- *Correspondence: Hua Tian, ; Antentor O. Hinton Jr, ; Melanie R. McReynolds,
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11
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Chiariello A, Valente S, Pasquinelli G, Baracca A, Sgarbi G, Solaini G, Medici V, Fantini V, Poloni TE, Tognocchi M, Arcaro M, Galimberti D, Franceschi C, Capri M, Salvioli S, Conte M. The expression pattern of GDF15 in human brain changes during aging and in Alzheimer's disease. Front Aging Neurosci 2023; 14:1058665. [PMID: 36698863 PMCID: PMC9869280 DOI: 10.3389/fnagi.2022.1058665] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/08/2022] [Indexed: 01/11/2023] Open
Abstract
Introduction Growth Differentiation Factor 15 (GDF15) is a mitochondrial-stress-responsive molecule whose expression strongly increases with aging and age-related diseases. However, its role in neurodegenerative diseases, including Alzheimer's disease (AD), is still debated. Methods We have characterized the expression of GDF15 in brain samples from AD patients and non-demented subjects (controls) of different ages. Results Although no difference in CSF levels of GDF15 was found between AD patients and controls, GDF15 was expressed in different brain areas and seems to be predominantly localized in neurons. The ratio between its mature and precursor form was higher in the frontal cortex of AD patients compared to age-matched controls (p < 0.05). Moreover, this ratio was even higher for centenarians (p < 0.01), indicating that aging also affects GDF15 expression and maturation. A lower expression of OXPHOS complexes I, III, and V in AD patients compared to controls was also noticed, and a positive correlation between GDF15 and IL-6 mRNA levels was observed. Finally, when GDF15 was silenced in vitro in dermal fibroblasts, a decrease in OXPHOS complexes transcript levels and an increase in IL-6 levels were observed. Discussion Although GDF15 seems not to be a reliable CSF marker for AD, it is highly expressed in aging and AD brains, likely as a part of stress response aimed at counteracting mitochondrial dysfunction and neuroinflammation.
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Affiliation(s)
- Antonio Chiariello
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Sabrina Valente
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Gianandrea Pasquinelli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Alessandra Baracca
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, Bologna, Italy
| | - Gianluca Sgarbi
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, Bologna, Italy
| | - Giancarlo Solaini
- Department of Biomedical and Neuromotor Sciences (DIBINEM), Laboratory of Biochemistry and Mitochondrial Pathophysiology, University of Bologna, Bologna, Italy
| | - Valentina Medici
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Milan, Italy
| | - Valentina Fantini
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Milan, Italy
| | - Tino Emanuele Poloni
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Milan, Italy
| | - Monica Tognocchi
- Department of Agriculture, Food and Environment, University of Pisa, Pisa, Italy
| | - Marina Arcaro
- Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Claudio Franceschi
- Department of Applied Mathematics of the Institute of ITMM, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Miriam Capri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy,Interdepartmental Centre “Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)”, University of Bologna, Bologna, Italy
| | - Stefano Salvioli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy,Interdepartmental Centre “Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)”, University of Bologna, Bologna, Italy,*Correspondence: Stefano Salvioli, ✉
| | - Maria Conte
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy,Interdepartmental Centre “Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate)”, University of Bologna, Bologna, Italy
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12
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Seminotti B, Brondani M, Ribeiro RT, Leipnitz G, Wajner M. Disturbance of Mitochondrial Dynamics, Endoplasmic Reticulum-Mitochondria Crosstalk, Redox Homeostasis, and Inflammatory Response in the Brain of Glutaryl-CoA Dehydrogenase-Deficient Mice: Neuroprotective Effects of Bezafibrate. Mol Neurobiol 2022; 59:4839-4853. [PMID: 35639256 DOI: 10.1007/s12035-022-02887-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/17/2022] [Indexed: 11/26/2022]
Abstract
Patients with glutaric aciduria type 1 (GA1), a neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) activity, commonly manifest acute encephalopathy associated with severe striatum degeneration and progressive cortical and striatal injury whose pathogenesis is still poorly known. We evaluated redox homeostasis, inflammatory response, mitochondrial biogenesis and dynamics, endoplasmic reticulum (ER)-mitochondria crosstalk, and ER stress in the brain of GCDH-deficient (Gcdh-/-) and wild-type (Gcdh+/+) mice fed a high Lys chow, which better mimics the human neuropathology mainly characterized by striatal lesions. Increased lipid peroxidation and altered antioxidant defenses, including decreased concentrations of reduced glutathione and increased activities of superoxide dismutase, catalase, and glutathione transferase, were observed in the striatum and cerebral cortex of Gcdh-/- mice. Augmented Iba-1 staining was also found in the dorsal striatum and neocortex, whereas the nuclear content of NF-κB was increased, and the cytosolic content of IκBα decreased in the striatum of the mutant animals, indicating a pro-inflammatory response. Noteworthy, in vivo treatment with the pan-PPAR agonist bezafibrate normalized these alterations. It was also observed that the ER-mitochondria crosstalk proteins VDAC1 and IP3R were reduced, whereas the ER stress protein DDIT3 was augmented in Gcdh-/- striatum, signaling disturbances of these processes. Finally, DRP1 content was elevated in the striatum of Gcdh-/- mice, indicating activated mitochondrial fission. We presume that some of these novel pathomechanisms may be involved in GA1 neuropathology and that bezafibrate should be tested as a potential adjuvant therapy for GA1.
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Affiliation(s)
- Bianca Seminotti
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Morgana Brondani
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rafael Teixeira Ribeiro
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio 21111, Porto Alegre, RS, 90035-003, Brazil
| | - Moacir Wajner
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio 21111, Porto Alegre, RS, 90035-003, Brazil.
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil.
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13
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Gentile A, Magnacca N, de Matteis R, Moreno M, Cioffi F, Giacco A, Lanni A, de Lange P, Senese R, Goglia F, Silvestri E, Lombardi A. Ablation of uncoupling protein 3 affects interrelated factors leading to lipolysis and insulin resistance in visceral white adipose tissue. FASEB J 2022; 36:e22325. [PMID: 35452152 DOI: 10.1096/fj.202101816rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 11/11/2022]
Abstract
The physiological role played by uncoupling protein 3 (UCP3) in white adipose tissue (WAT) has not been elucidated so far. In the present study, we evaluated the impact of the absence of the whole body UCP3 on WAT physiology in terms of ability to store triglycerides, oxidative capacity, response to insulin, inflammation, and adipokine production. Wild type (WT) and UCP3 Knockout (KO) mice housed at thermoneutrality (30°C) have been used as the animal model. Visceral gonadic WAT (gWAT) from KO mice showed an impaired capacity to store triglycerides (TG) as indicated by its lowered weight, reduced adipocyte diameter, and higher glycerol release (index of lipolysis). The absence of UCP3 reduces the maximal oxidative capacity of gWAT, increases mitochondrial free radicals, and activates ER stress. These processes are associated with increased levels of monocyte chemoattractant protein-1 and TNF-α. The response of gWAT to in vivo insulin administration, revealed by (ser473)-AKT phosphorylation, was blunted in KO mice, with a putative role played by eif2a, JNK, and inflammation. Variations in adipokine levels in the absence of UCP3 were observed, including reduced adiponectin levels both in gWAT and serum. As a whole, these data indicate an important role of UCP3 in regulating the metabolic functionality of gWAT, with its absence leading to metabolic derangement. The obtained results help to clarify some aspects of the association between metabolic disorders and low UCP3 levels.
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Affiliation(s)
| | - Nunzia Magnacca
- Department of Biology, University of Naples Federico II, Naples, Italy
| | - Rita de Matteis
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
| | - Maria Moreno
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Federica Cioffi
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Antonia Giacco
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Antonia Lanni
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Pieter de Lange
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Rosalba Senese
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Fernando Goglia
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Elena Silvestri
- Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Assunta Lombardi
- Department of Biology, University of Naples Federico II, Naples, Italy
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14
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Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules 2022; 12:biom12040542. [PMID: 35454131 PMCID: PMC9030615 DOI: 10.3390/biom12040542] [Citation(s) in RCA: 336] [Impact Index Per Article: 112.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/06/2023] Open
Abstract
Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.
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15
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Cai B, Ma M, Zhang J, Wang Z, Kong S, Zhou Z, Lian L, Zhang J, Li J, Wang Y, Li H, Zhang X, Nie Q. LncEDCH1 improves mitochondrial function to reduce muscle atrophy by interacting with SERCA2. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:319-334. [PMID: 35024244 PMCID: PMC8717430 DOI: 10.1016/j.omtn.2021.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022]
Abstract
Skeletal muscle is a regulator of the body's energy expenditure and metabolism. Abnormal regulation of skeletal muscle-specific genes leads to various muscle diseases. Long non-coding RNAs (lncRNAs) have been demonstrated to play important roles in muscle growth and muscle atrophy. To explore the potential function of muscle-associated lncRNA, we analyzed our previous RNA-sequencing data and selected the lncRNA (LncEDCH1) as the research object. In this study, we report that LncEDCH1 is specifically enriched in skeletal muscle, and its transcriptional activity is positively regulated by transcription factor SP1. LncEDCH1 regulates myoblast proliferation and differentiation in vitro. In vivo, LncEDCH1 reduces intramuscular fat deposition, activates slow-twitch muscle phenotype, and inhibits muscle atrophy. Mechanistically, LncEDCH1 binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) protein to enhance SERCA2 protein stability and increase SERCA2 activity. Meanwhile, LncEDCH1 improves mitochondrial efficiency possibly through a SERCA2-mediated activation of the AMPK pathway. Our findings provide a strategy for using LncEDCH1 as an effective regulator for the treatment of muscle atrophy and energy metabolism.
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Affiliation(s)
- Bolin Cai
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Manting Ma
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Jing Zhang
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Zhijun Wang
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Shaofen Kong
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Zhen Zhou
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Ling Lian
- National Engineering Laboratory for Animal Breeding and MOA Key Laboratory of Animal Genetics and Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Jiannan Zhang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Juan Li
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Yajun Wang
- Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China
| | - Hongmei Li
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Xiquan Zhang
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
| | - Qinghua Nie
- Lingnan Guangdong Laboratory of Modern Agriculture & State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.,Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, Guangdong 510642, China
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16
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Zhao GD, Gao R, Hou XT, Zhang H, Chen XT, Luo JQ, Yang HF, Chen T, Shen X, Yang SC, Wu CL, Huang G. Endoplasmic Reticulum Stress Mediates Renal Tubular Vacuolation in BK Polyomavirus-Associated Nephropathy. Front Endocrinol (Lausanne) 2022; 13:834187. [PMID: 35464062 PMCID: PMC9027570 DOI: 10.3389/fendo.2022.834187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/04/2022] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE This study aimed to explore the molecular mechanism of cytoplasmic vacuolation caused by BK polyomavirus (BKPyV) and thus search for potential target for drug repurposing. METHODS Morphological features of BK polyomavirus-associated nephropathy (BKPyVAN) were studied under light and electron microscopes. Microarray datasets GSE75693, GSE47199, and GSE72925 were integrated by ComBat, and differentially expressed genes (DEGs) were analyzed using limma. Furthermore, the endoplasmic reticulum (ER)-related genes obtained from GenCLiP 2.0 were intersected with DEGs. GO and KEGG enrichment pathways were performed with intersection genes by R package clusterProfiler. The single-cell RNA sequencing (scRNA-seq) from a BKPyVAN recipient was analyzed with a dataset (GSE140989) downloaded from Gene Expression Omnibus (GEO) as control for gene set variation analysis (GSVA). Immunohistochemistry and electron microscopy of kidney sections from drug-induced ERS mouse models were performed to explore the association of ERS and renal tubular vacuolation. Protein-protein interaction (PPI) network of the intersection genes was constructed to identify hub target. AutoDock was used to screen Food and Drug Administration (FDA)-approved drugs that potentially targeted hub gene. RESULTS Light and electron microscopes exhibited obvious intranuclear inclusions, vacuoles, and virus particles in BKPyV-infected renal tubular cells. Transcriptome analysis revealed 629 DEGs between samples of BKPyVAN and stable transplanted kidneys, of which 16 were ER-associated genes. GO analysis with the intersection genes illustrated that ERS-related pathways were significantly involved, and KEGG analysis showed a prominent enrichment of MAPK, Toll-like receptor, and chemokine signaling pathways. GSVA analysis of the proximal tubule revealed similar pathways enrichment. An electron microscope image of the kidney from ERS mouse models showed an obvious renal tubular vacuolation with prominent activation of ERS markers verified by immunohistochemistry. Furthermore, DDIT3 was identified as the hub gene based on PPI analysis, and ZINCOOOOO1531009 (Risedronate) was indicated to be a potential drug for DDIT3. CONCLUSION ERS was involved in renal tubular cytoplasmic vacuolation in BKPyVAN recipients. Risedronate was screened as a potential drug for BKPyVAN by targeting DDIT3.
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Affiliation(s)
- Guo-Dong Zhao
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rong Gao
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiao-Tao Hou
- Department of Renal Pathology, King Medical Diagnostics Center, Guangzhou, China
| | - Hui Zhang
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu-Tao Chen
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin-Quan Luo
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hui-Fei Yang
- Department of Pathology, Fuda Cancer Hospital·Jinan University, Guangzhou, China
| | - Tong Chen
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xue Shen
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shi-Cong Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Cheng-Lin Wu
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Gang Huang, ; Cheng-Lin Wu,
| | - Gang Huang
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Gang Huang, ; Cheng-Lin Wu,
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17
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Huang TT, Sun WJ, Liu HY, Ma HL, Cui BX. p66Shc-mediated oxidative stress is involved in gestational diabetes mellitus. World J Diabetes 2021; 12:1894-1907. [PMID: 34888014 PMCID: PMC8613666 DOI: 10.4239/wjd.v12.i11.1894] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/29/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is associated with a heightened level of oxidative stress, which is characterized by the overproduction of reactive oxygen species (ROS) from mitochondria. Previous studies showed that mitochondrial dysfunction is regulated by dynamin-related protein 1 (Drp1) and p66Shc in GDM.
AIM The aim was to investigate the expression of Drp1 and p66Shc and their possible mechanisms in the pathogenesis of GDM.
METHODS A total of 30 pregnant women, 15 with GDM and 15 without GDM, were enrolled. Peripheral blood mononuclear cells and placental tissue were collected. The human JEG3 trophoblast cell line was cultivated in 5.5 mmol/L or 30 mmol/L glucose and transfected with wild-type (wt)-p66Shc and p66Shc siRNA. P66Shc and Drp1 mRNA levels were detected by quantitative real-time polymerase chain reaction. The expression of p66Shc and Drp1 was assayed by immunohistochemistry and western blotting. ROS was assayed by dihydroethidium staining.
RESULTS The p66Shc mRNA level was increased in the serum (P < 0.01) and placentas (P < 0.01) of women with GDM, and the expression of Drp1 mRNA and protein were also increased in placentas (P < 0.05). In JEG3 cells treated with 30 mmol/L glucose, the mRNA and protein expression of p66Shc and Drp1 were increased at 24 h (both P < 0.05), 48 h (both P < 0.01) and 72 h (both P < 0.001). ROS expression was also increased. High levels of Drp1 and ROS expression were detected in JEG3 cells transfected with wt-p66Shc (P < 0.01), and low levels were detected in JEG3 cells transfected with p66Shc siRNA (P < 0.05).
CONCLUSION The upregulated expression of Drp1 and p66shc may contribute to the occurrence and development of GDM. Regulation of the mitochondrial fusion-fission balance could be a novel strategy for GDM treatment.
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Affiliation(s)
- Ting-Ting Huang
- Cheeloo College of Medicine, Shandong University, Jinan 250000, Shandong Province, China
- Department of Obstetrics, Taian City Central Hospital, Taian 271000, Shandong Province, China
| | - Wen-Juan Sun
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250000, Shandong Province, China
| | - Hai-Ying Liu
- Department of Obstetrics and Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266000, Shandong Province, China
| | - Hong-Li Ma
- Department of Obstetrics, Taian City Central Hospital, Taian 271000, Shandong Province, China
| | - Bao-Xia Cui
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250013, Shandong Province, China
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18
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Xie Q, Li Z, Liu Y, Zhang D, Su M, Niitsu H, Lu Y, Coffey RJ, Bai M. Translocator protein-targeted photodynamic therapy for direct and abscopal immunogenic cell death in colorectal cancer. Acta Biomater 2021; 134:716-729. [PMID: 34329783 DOI: 10.1016/j.actbio.2021.07.052] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023]
Abstract
Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we induced ICD in colorectal cancer (CRC) cell lines in vitro and in vivo by targeting the 18 kDa translocator protein (TSPO), a mitochondrial receptor overexpressed in CRC. Photodynamic therapy (PDT) using a TSPO-targeted photosensitizer, IR700DX-6T, caused effective apoptotic cell death in fourteen CRC cell lines. In a syngeneic immunocompetent CRC mouse model, the growth of tumors subjected to TSPO-PDT was greatly suppressed. Remarkably, untreated tumors in the opposing flank also showed marked growth suppression. Dendritic and CD8+ T cells were activated after TSPO-PDT treatment, accompanied by decreased Treg cells in both treated and non-treated tumors. In addition, a cancer vaccine developed from TSPO-PDT produced a significant tumor inhibition effect. These results indicate that TSPO-PDT could not only directly suppress tumor growth but also dramatically provoke host anti-tumor immunity, highlighting the potential of TSPO-PDT as a successful therapeutic for CRC that exhibits systemic effects. STATEMENT OF SIGNIFICANCE: Abscopal effect is an attractive cancer therapeutic effect referring to tumor regression at a location distant from the primary treatment site. Immunogenic cell death (ICD) offers a mechanistic link between the primary and remote therapeutic effects by activating favorable anti-tumor immune responses. In this study, we report a new therapeutic approach that can reduce the growth of multiple CRC cell lines by inducing ICD. Notably, a direct and abscopal effect was observed in mouse tumor-derived MC38 cells when injected into syngeneic immunocompetent mice. If comparable effects could be achieved in humans, it would establish a novel paradigm for treating micro- and macro-metastasis.
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19
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Oliveira KAD, Araújo HN, Lima TID, Oliveira AG, Favero-Santos BC, Guimarães DSP, Freitas PAD, Neves RDJD, Vasconcelos RP, Almeida MGGD, Ramos MV, Silveira LR, Oliveira ACD. Phytomodulatory proteins isolated from Calotropis procera latex promote glycemic control by improving hepatic mitochondrial function in HepG2 cells. Saudi Pharm J 2021; 29:1061-1069. [PMID: 34588851 PMCID: PMC8463474 DOI: 10.1016/j.jsps.2021.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 07/04/2021] [Indexed: 12/03/2022] Open
Abstract
The medicinal uses of Calotropis procera are diverse, yet some of them are based on effects that still lack scientific support. Control of diabetes is one of them. Recently, latex proteins from C. procera latex (LP) have been shown to promote in vivo glycemic control by the inhibition of hepatic glucose production via AMP-activated protein kinase (AMPK). Glycemic control has been attributed to an isolated fraction of LP (CpPII), which is composed of cysteine peptidases (95%) and osmotin (5%) isoforms. Those proteins are extensively characterized in terms of chemistry, biochemistry and structural aspects. Furthermore, we evaluated some aspects of the mitochondrial function and cellular mechanisms involved in CpPII activity. The effect of CpPII on glycemic control was evaluated in fasting mice by glycemic curve and glucose and pyruvate tolerance tests. HepG2 cells was treated with CpPII, and cell viability, oxygen consumption, PPAR activity, production of lactate and reactive oxygen species, mitochondrial density and protein and gene expression were analyzed. CpPII reduced fasting glycemia, improved glucose tolerance and inhibited hepatic glucose production in control animals. Additionally, CpPII increased the consumption of ATP-linked oxygen and mitochondrial uncoupling, reduced lactate concentration, increased protein expression of mitochondrial complexes I, III and V, and activity of peroxisome-proliferator-responsive elements (PPRE), reduced the presence of reactive oxygen species (ROS) and increased mitochondrial density in HepG2 cells by activation of AMPK/PPAR. Our findings strongly support the medicinal use of the plant and suggest that CpPII is a potential therapy for prevention and/or treatment of type-2 diabetes. A common epitope sequence shared among the proteases and osmotin is possibly the responsible for the beneficial effects of CpPII.
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Key Words
- AMPK, AMP-activated kinase protein
- AUC, Area under the curve
- Bioactive proteins
- CTL, Control
- Calotropis procera
- CpPII, Major peptidase fraction treated with iodoacetamide
- DHE, Dihydroethidium
- DMEM, Dulbecco’s minimal essential medium
- DMSO, Dimethyl sulfoxide
- FCCP, Oligomycin carbonyl cyanide 4 (trifluoromethoxy) phenylhydrazine
- Folk medicine
- Glycemia
- HGP, Hepatic glucose production
- LP, Soluble latex proteins from Calotropis procera
- Latex
- MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- OCR, Oxygen consumption rate
- OXPHOS, Oxidative phosphorylation
- PPAR, Peroxisome proliferator-activated receptor
- PPRE, PPAR response element
- ROS, Reactive oxygen species
- TBS-T, Tris buffered saline solution containing 0.1% Tween 20
- UCP2, Mitochondrial uncoupling protein 2
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Ariclecio Cunha de Oliveira
- Superior Institute of Biomedical Sciences, State University of Ceara, Fortaleza, Brazil
- Corresponding author.at: Superior Institute of Biomedical Sciences, State University of Ceara, Fortaleza, Ceara, Brazil.
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20
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Communications between Mitochondria and Endoplasmic Reticulum in the Regulation of Metabolic Homeostasis. Cells 2021; 10:cells10092195. [PMID: 34571844 PMCID: PMC8468463 DOI: 10.3390/cells10092195] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondria associated membranes (MAM), which are the contact sites between endoplasmic reticulum (ER) and mitochondria, have emerged as an important hub for signaling molecules to integrate the cellular and organelle homeostasis, thus facilitating the adaptation of energy metabolism to nutrient status. This review explores the dynamic structural and functional features of the MAM and summarizes the various abnormalities leading to the impaired insulin sensitivity and metabolic diseases.
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21
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Leskelä S, Hoffmann D, Rostalski H, Huber N, Wittrahm R, Hartikainen P, Korhonen V, Leinonen V, Hiltunen M, Solje E, Remes AM, Haapasalo A. FTLD Patient-Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62. Mol Neurobiol 2021; 58:5438-5458. [PMID: 34328616 PMCID: PMC8599259 DOI: 10.1007/s12035-021-02475-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/25/2021] [Indexed: 11/25/2022]
Abstract
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive cognitive dysfunction and frontal and temporal atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD, but pathogenic mechanisms underlying FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of FTLD patient–derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors. Fibroblasts from C9-HRE carriers were found to produce RNA foci, but no dipeptide repeat proteins, and they showed unchanged levels of C9orf72 mRNA transcripts. The main protein degradation pathways, the ubiquitin–proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to ATP production, were significantly reduced in the FTLD patient–derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that FTLD patient–derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing FTLD patient–derived fibroblasts as a platform for biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration.
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Affiliation(s)
- Stina Leskelä
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211, Kuopio, Finland
| | - Dorit Hoffmann
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211, Kuopio, Finland
| | - Hannah Rostalski
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211, Kuopio, Finland
| | - Nadine Huber
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211, Kuopio, Finland
| | - Rebekka Wittrahm
- Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211, Kuopio, Finland
| | - Päivi Hartikainen
- Neuro Center, Neurology, Kuopio University Hospital, 70029, Kuopio, Finland
| | - Ville Korhonen
- Neuro Center, Neurosurgery, Kuopio University Hospital, 70029, Kuopio, Finland
- Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland
| | - Ville Leinonen
- Neuro Center, Neurosurgery, Kuopio University Hospital, 70029, Kuopio, Finland
- Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland
| | - Mikko Hiltunen
- Institute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211, Kuopio, Finland
| | - Eino Solje
- Neuro Center, Neurology, Kuopio University Hospital, 70029, Kuopio, Finland
- Institute of Clinical Medicine - Neurology, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland
| | - Anne M Remes
- Unit of Clinical Neuroscience, Neurology, University of Oulu, P.O. Box 8000, 90014, Oulu, Finland
- MRC Oulu, Oulu University Hospital, P.O. Box 8000, 90014, Oulu, Finland
| | - Annakaisa Haapasalo
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, 70211, Kuopio, Finland.
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22
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Bramlage KS, Bhattacharjee J, Kirby M, Myronovych A, Gupta R, Gonzalez RMS, Xanthakos S, Bove K, Kohli R. A Diet High in Fat and Fructose Induces Early Hepatic Mitochondrial Aging. J Pediatr Gastroenterol Nutr 2021; 73:99-102. [PMID: 34135298 PMCID: PMC8549102 DOI: 10.1097/mpg.0000000000003068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT To investigate the effect of high fructose diet on ultrastructure and content of hepatic mitochondria, we randomized 6-8 weeks old male C57Bl6/J mice to ad lib chow or high-fat-high-fructose (HF2) diet for 32 weeks. HF2-fed mice gained more weight, had higher plasma alanine aminotransferase, and fasting glucose levels and increased hepatic triglyceride content at all time points compared to chow-fed mice. HF2-fed mice had lower mitochondrial to nuclear DNA ratio compared to chow-fed mice. HF2-fed mice had lower average mitochondrial surface area and the number of mitochondria compared to chow-fed mice. HF2-fed mice had higher expression of the hepatic endoplasmic reticulum stress marker Chop, compared to chow-fed mice. A diet high in fat and fructose leads to enhanced hepatic mitochondrial aging, depletion, and dysfunction, which may be important determinants of nonalcoholic steatohepatitis pathogenesis.
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Affiliation(s)
- Kristin S. Bramlage
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Jashdeep Bhattacharjee
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA
| | - Michelle Kirby
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Andriy Myronovych
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Rohun Gupta
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA
| | | | - Stavra Xanthakos
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Kevin Bove
- Department of Pediatrics, Division of Pathology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH
| | - Rohit Kohli
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital Los Angeles, Los Angeles, CA
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23
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Xu LB, Xiong J, Zhang YH, Dai Y, Ren XP, Ren YJ, Han D, Wei SH, Qi M. miR‑205‑3p promotes lung cancer progression by targeting APBB2. Mol Med Rep 2021; 24:588. [PMID: 34165160 PMCID: PMC8222966 DOI: 10.3892/mmr.2021.12227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 03/29/2021] [Indexed: 12/29/2022] Open
Abstract
Non-small cell lung cancer (NSCLC), a leading cause of cancer-associated mortality, has resulted in low survival rates and a high mortality worldwide. Accumulating evidence has suggested that microRNAs (miRs) play critical roles in the regulation of cancer progression and the present study aimed to explore the underlying mechanism of miR-205 in NSCLC. Reverse transcription-quantitative PCR was performed, which determined that miR-205 expression was upregulated in NSCLC, and the present study detected the upregulation of miR-205-3p in a number of NSCLC cell lines and NSCLC tissues. In addition, the mediation of amyloid β precursor protein-binding family B member 2 (APBB2) by miR-205-3p was demonstrated. Moreover, miR-205-3p was predicted to directly target the 3′untranslated region of APBB2, which was confirmed using a dual-luciferase reporter assay. It was found that lentivirus mediated-APBB2 knockdown could promote cellular viability and suppress apoptosis in NSCLC cells, as determined via MTT, TUNEL and flow cytometry assays. Thus, the current findings highlighted the potential promotive impact of miR-205-3p on NSCLC processes and may provide theoretical evidence for miR-205-3p as a potential clinical gene therapy target.
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Affiliation(s)
- Ling-Bin Xu
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Jie Xiong
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Ya-Hui Zhang
- Department of Orthopaedics, Xi'an Daxing Hospital, Xi'an, Shaanxi 710016, P.R. China
| | - Yun Dai
- Department of Thoracic Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Xiao-Ping Ren
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Ya-Juan Ren
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Dong Han
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Sheng-Hong Wei
- Department of Pulmonary and Critical Care Medicine No. 2, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Min Qi
- Imaging Center, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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24
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Dokukina IV, Yamashev MV, Samarina EA, Tilinova OM, Grachev EA. Calcium-dependent insulin resistance in hepatocytes: mathematical model. J Theor Biol 2021; 522:110684. [PMID: 33794287 DOI: 10.1016/j.jtbi.2021.110684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 03/07/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023]
Abstract
Hepatocyte insulin resistance is one of the early factors of developing type II diabetes. If insulin resistance is treated early, type II diabetes could be prevented. In recent years, scientists have been conducting extensive research on the underlying issues on a cellular and molecular level. It was found that the modulation of IP3-receptors, the mitochondrial ability to form the mitochondria-associated membranes (MAMs) and the endoplasmic reticulum stress during Ca2+ signaling play a key role in hepatocyte being able to maintain euglycemia and provide metabolic flexibility. However, researchers cannot agree on what factor is the key one in resulting in insulin resistance. In this work, we propose a mathematical model of Ca2+ signaling. We included in the model all the major contributors of a proper Ca2+ signaling during both the fasting and the postprandial state. Our modeling results are in good agreement with available experimental data. The analysis of modeling results suggests that MAMs dysfunction alone cannot result in abnormal Ca2+ signaling and the wrong modulation of IP3-receptors is a more definite reason. However, both the MAMs dysfunction and the IP3 signaling dysregulation combined can lead to a robust Ca2+ signal and improper glucose release. In addition, our model results suggest a strong dependence of Ca2+ oscillations pattern on morphological characteristics of the ER and the mitochondria.
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Affiliation(s)
- Irina V Dokukina
- Sarov Physical and Technical Institute, National Research Nuclear University MEPhI, Sarov, Russian Federation.
| | | | - Ekaterina A Samarina
- Sarov Physical and Technical Institute, National Research Nuclear University MEPhI, Sarov, Russian Federation
| | - Oksana M Tilinova
- Sarov Physical and Technical Institute, National Research Nuclear University MEPhI, Sarov, Russian Federation
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25
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The Metabolic Role of GRK2 in Insulin Resistance and Associated Conditions. Cells 2021; 10:cells10010167. [PMID: 33467677 PMCID: PMC7830135 DOI: 10.3390/cells10010167] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes.
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26
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Sun Y, Ding S. ER-Mitochondria Contacts and Insulin Resistance Modulation through Exercise Intervention. Int J Mol Sci 2020; 21:ijms21249587. [PMID: 33339212 PMCID: PMC7765572 DOI: 10.3390/ijms21249587] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022] Open
Abstract
The endoplasmic reticulum (ER) makes physical contacts with mitochondria at specific sites, and the hubs between the two organelles are called mitochondria-associated ER membranes (MAMs). MAMs are known to play key roles in biological processes, such as intracellular Ca2+ regulation, lipid trafficking, and metabolism, as well as cell death, etc. Studies demonstrated that dysregulation of MAMs significantly contributed to insulin resistance. Alterations of MAMs’ juxtaposition and integrity, impaired expressions of insulin signaling molecules, disruption of Ca2+ homeostasis, and compromised metabolic flexibility are all actively involved in the above processes. In addition, exercise training is considered as an effective stimulus to ameliorate insulin resistance. Although the underlying mechanisms for exercise-induced improvement in insulin resistance are not fully understood, MAMs may be critical for the beneficial effects of exercise.
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Affiliation(s)
- Yi Sun
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China;
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Shuzhe Ding
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China;
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China
- Correspondence:
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27
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A mechanism of perhexiline's cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway. Chem Biol Interact 2020; 334:109353. [PMID: 33309543 DOI: 10.1016/j.cbi.2020.109353] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/20/2020] [Accepted: 12/05/2020] [Indexed: 12/22/2022]
Abstract
Perhexiline is a coronary vasodilator for angina treatment that was first developed in the 1960s. Perhexiline enjoyed worldwide success before reports of severe side effects, such as hepatotoxicity and neurotoxicity, caused its withdrawal from most of the markets. The underlying mechanism of the cytotoxicity of perhexiline, however, is not yet well understood. Here we demonstrated that perhexiline induced cellular damage in primary human hepatocytes, HepaRG cells and HepG2 cells. Analysis of gene and protein expression levels of endoplasmic reticulum (ER) stress markers showed that perhexiline caused ER stress in primary human hepatocytes and HepG2 cells. The splicing of XBP1 mRNA, a hallmark of ER stress, was observed upon perhexiline treatment. Using Gluc-Fluc-HepG2 cell line, we demonstrated that protein secretion was impaired upon perhexiline treatment, suggesting functional deficits in ER. Inhibition of ER stress using ER inhibitor 4-PBA or salubrinal attenuated the cytotoxicity of perhexiline. Directly knocking down ATF4 using siRNA also partially rescued HepG2 cells upon perhexiline exposure. In addition, inhibition of ER stress using either inhibitors or siRNA transfection attenuated perhexiline-induced increase in caspase 3/7 activity, indicating that ER stress contributed to perhexiline-induced apoptosis. Moreover, perhexiline treatment resulted in activation of p38 and JNK signaling pathways, two branches of MAPK cascade. Pre-treating HepG2 cells with p38 inhibitor SB239063 attenuated perhexiline-induced apoptosis and cell death. The inhibitor also prevented the activation of CHOP and ATF4. Overall, our study demonstrated that ER stress is one important mechanism underlying the hepatotoxicity of perhexiline, and p38 signaling pathway contributes to this process. Our finding shed light on the role of both ER stress and p38 signaling pathway in drug-induced liver injury.
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28
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Nakagawa Y, Yamada S. A novel hypothesis on metal dyshomeostasis and mitochondrial dysfunction in amyotrophic lateral sclerosis: Potential pathogenetic mechanism and therapeutic implications. Eur J Pharmacol 2020; 892:173737. [PMID: 33220280 DOI: 10.1016/j.ejphar.2020.173737] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 10/27/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunctions resulting from the loss of upper (UMNs) and lower (LMNs) motor neurons. While ALS symptoms are coincidental with pathological changes in LMNs and UMNs, the causal relationship between the two is unclear. For example, research on the extra-motor symptoms associated with this condition suggests that an imbalance of metals, including copper, zinc, iron, and manganese, is initially induced in the sensory ganglia due to a malfunction of metal binding proteins and transporters. It is proposed that the resultant metal dyshomeostasis may promote mitochondrial dysfunction in the satellite glial cells of these sensory ganglia, causing sensory neuron disturbances and sensory symptoms. Sensory neuron hyperactivation can result in LMN impairments, while metal dyshomeostasis in spinal cord and brain stem parenchyma induces mitochondrial dysfunction in LMNs and UMNs. These events could prompt intracellular calcium dyshomeostasis, pathological TDP-43 formation, and reactive microglia with neuroinflammation, which in turn activate the apoptosis signaling pathways within the LMNs and UMNs. Our model suggests that the degeneration of LMNs and UMNs is incidental to the metal-induced changes in the spinal cord and brain stem. Over time psychiatric symptoms may appear as the metal dyshomeostasis and mitochondrial dysfunction affect other brain regions, including the reticular formation, hippocampus, and prefrontal cortex. It is proposed that metal dyshomeostasis in combination with mitochondrial dysfunction could be the underlying mechanism responsible for the initiation and progression of the pathological changes associated with both the motor and extra-motor symptoms of ALS.
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Affiliation(s)
- Yutaka Nakagawa
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
| | - Shizuo Yamada
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
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Zhuan B, Wang X, Wang MD, Li ZC, Yuan Q, Xie J, Yang Z. Hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated endoplasmic reticulum stress. Aging (Albany NY) 2020; 12:23684-23697. [PMID: 33221740 PMCID: PMC7762493 DOI: 10.18632/aging.103892] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 07/23/2020] [Indexed: 12/16/2022]
Abstract
Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) dysfunction. However, the underlying mechanisms of PASMC dysfunction remain largely unknown. Here, we show that mitochondrial fragmentation contributes to PASMC dysfunction through enhancement of endoplasmic reticulum (ER) stress. PASMC dysfunction accompanied by mitochondrial fragmentation and ER stress was observed in the pulmonary arteries of hypoxia-induced rats with PAH, as well as isolated PASMCs under hypoxia. Treatment with Mdivi-1 inhibited mitochondrial fragmentation and ER stress and improved PASMC function in isolated PASMCs under hypoxia, while Drp1 overexpression increased mitochondrial fragmentation and ER stress, impairing PASMC function in isolated PASMCs under normoxia. However, inhibition of ER stress using ER stress inhibitors showed a negligible effect on mitochondrial morphology but improved PASMC function during hypoxia. Additionally, we found that mitochondrial fragmentation-promoted ER stress was dependent on mitochondrial reactive oxygen species. Furthermore, inhibition of mitochondrial fragmentation using Mdivi-1 attenuated mitochondrial fragmentation and ER stress in hypoxic PASMCs and improved the pulmonary artery smooth muscle function in hypoxic rats. These results suggest that hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated ER stress and that mitochondrial morphology is a potential target for treatment of hypoxia-induced pulmonary artery smooth muscle dysfunction.
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Affiliation(s)
- Bing Zhuan
- Department of Respiratory Medicine, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750000, China
| | - Xi Wang
- Department of Respiratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Ming-Deng Wang
- Department of Intensive Care Unit, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Zhi-Cai Li
- Department of Respiratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Qun Yuan
- Department of Respiratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Jun Xie
- Department of Thoracic Surgery, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Zhao Yang
- Department of Respiratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
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30
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Zhang J, Ren Y, Bi J, Wang M, Zhang L, Wang T, Wei S, Mou X, Lv Y, Wu R. Involvement of kindlin-2 in irisin's protection against ischaemia reperfusion-induced liver injury in high-fat diet-fed mice. J Cell Mol Med 2020; 24:13081-13092. [PMID: 32954626 PMCID: PMC7701503 DOI: 10.1111/jcmm.15910] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 08/26/2020] [Accepted: 09/03/2020] [Indexed: 12/23/2022] Open
Abstract
Liver steatosis is associated with increased ischaemia reperfusion (I/R) injury. Our previous studies have shown that irisin, an exercise-induced hormone, mitigates I/R injury via binding to αVβ5 integrin. However, the effect of irisin on I/R injury in steatotic liver remains unknown. Kindlin-2 directly interacts with β integrin. We therefore suggest that irisin protects against I/R injury in steatotic liver via a kindlin-2 dependent mechanism. To study this, hepatic steatosis was induced in male adult mice by feeding them with a 60% high-fat diet (HFD). At 12 weeks after HFD feeding, the mice were subjected to liver ischaemia by occluding partial (70%) hepatic arterial/portal venous blood for 60 minutes, which was followed by 24 hours reperfusion. Our results showed HFD exaggerated I/R-induced liver injury. Irisin (250 μg/kg) administration at the beginning of reperfusion attenuated liver injury, improved mitochondrial function, and reduced oxidative and endoplasmic reticulum stress in HFD-fed mice. However, kindlin-2 inhibition by RNAi eliminated irisin's direct effects on cultured hepatocytes. In conclusion, irisin attenuates I/R injury in steatotic liver via a kindlin-2 dependent mechanism.
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Affiliation(s)
- Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Lin Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Shasha Wei
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Xingyi Mou
- Zonglian CollegeXi’an Jiaotong University Health Science CenterXi’anChina
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
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31
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Jackisch L, Murphy AM, Kumar S, Randeva H, Tripathi G, McTernan PG. Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes. J Clin Endocrinol Metab 2020; 105:5837767. [PMID: 32413131 DOI: 10.1210/clinem/dgaa258] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 05/12/2020] [Indexed: 12/29/2022]
Abstract
CONTEXT Dysfunctional endoplasmic reticulum (ER) and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date, insight into this dynamic relationship has not been characterized in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. METHODS Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP), and dynamics. RESULTS ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24 h: 23%↑; 48 h: 68%↑, P < 0.001; 72 h: 136%↑, P < 0.001). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganization of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (P < 0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, P < 0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. CONCLUSION These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess-induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.
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Affiliation(s)
- Laura Jackisch
- Warwick Medical School, University of Warwick, UHCW, Coventry, UK
| | - Alice M Murphy
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Sudhesh Kumar
- Warwick Medical School, University of Warwick, UHCW, Coventry, UK
| | - Harpal Randeva
- Warwick Medical School, University of Warwick, UHCW, Coventry, UK
| | - Gyanendra Tripathi
- Human Sciences Research Centre, College of Life and Natural Sciences, University of Derby, Derby, UK
| | - Philip G McTernan
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
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32
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Sasi USS, Ganapathy S, Palayyan SR, Gopal RK. Mitochondria Associated Membranes (MAMs): Emerging Drug Targets for Diabetes. Curr Med Chem 2020; 27:3362-3385. [PMID: 30747057 DOI: 10.2174/0929867326666190212121248] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 01/01/2019] [Accepted: 02/04/2019] [Indexed: 12/13/2022]
Abstract
MAMs, the physical association between the Endoplasmic Reticulum (ER) and mitochondria are, functional domains performing a significant role in the maintenance of cellular homeostasis. It is evolving as an important signaling center that coordinates nutrient and hormonal signaling for the proper regulation of hepatic insulin action and glucose homeostasis. Moreover, MAMs can be considered as hot spots for the transmission of stress signals from ER to mitochondria. The altered interaction between ER and mitochondria results in the amendment of several insulin-sensitive tissues, revealing the role of MAMs in glucose homeostasis. The development of mitochondrial dysfunction, ER stress, altered lipid and Ca2+ homeostasis are typically co-related with insulin resistance and β cell dysfunction. But little facts are known about the role played by these stresses in the development of metabolic disorders. In this review, we highlight the mechanisms involved in maintaining the contact site with new avenues of investigations for the development of novel preventive and therapeutic targets for T2DM.
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Affiliation(s)
- U S Swapna Sasi
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIRNational Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sindhu Ganapathy
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIRNational Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India
| | - Salin Raj Palayyan
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIRNational Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Raghu K Gopal
- Biochemistry and Molecular Mechanism Laboratory, Agro-processing and Technology Division, CSIRNational Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala 695019, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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33
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The Impact of Sugar-Sweetened Beverage Consumption on the Liver: A Proteomics-based Analysis. Antioxidants (Basel) 2020; 9:antiox9070569. [PMID: 32630236 PMCID: PMC7402188 DOI: 10.3390/antiox9070569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/15/2020] [Accepted: 06/19/2020] [Indexed: 12/24/2022] Open
Abstract
Cardiometabolic complications such as the metabolic syndrome and Type 2 Diabetes Mellitus (T2DM) are major causes of global morbidity and mortality. As sugar-sweetened beverages (SSBs) are implicated in this process, this study aimed to obtain greater mechanistic insights. Male Wistar rats (~200 g) were gavaged with a local SSB every day for a period of six months while the control group was gavaged with an iso-volumetric amount of water. Experimental dosages were calculated according to the surface area-to-volume ratio and were equivalent to 125 mL/day (in human terms). A proteomic analysis was performed on isolated liver samples and thereafter, markers of endoplasmic reticulum (ER) stress, antioxidant/oxidant capacity, calcium regulation, and mitochondrial functionality were assessed. These data show that SSB consumption resulted in (a) the induction of mild hepatic ER stress; (b) altered hepatic mitochondrial dynamics; and (c) perturbed calcium handling across mitochondria-associated ER membranes. Despite significant changes in markers of ER stress, the antioxidant response and calcium handling (proteomics data), the liver is able to initiate adaptive responses to counteract such stressors. However, the mitochondrial data showed increased fission and decreased fusion that may put the organism at risk for developing insulin resistance and T2DM in the longer term.
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34
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Seminotti B, Leipnitz G, Karunanidhi A, Kochersperger C, Roginskaya VY, Basu S, Wang Y, Wipf P, Van Houten B, Mohsen AW, Vockley J. Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. Hum Mol Genet 2020; 28:928-941. [PMID: 30445591 PMCID: PMC6400046 DOI: 10.1093/hmg/ddy403] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 12/12/2022] Open
Abstract
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid β-oxidation. Patients present with heterogeneous clinical phenotypes affecting heart, liver and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD-deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain (RC) function, increased reactive oxygen species (ROS) production and altered mitochondrial function and signaling pathways in a variety of VLCAD-deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved RC function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD-deficient patients.
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Affiliation(s)
- Bianca Seminotti
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.,Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Guilhian Leipnitz
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.,Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Anuradha Karunanidhi
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine Kochersperger
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Vera Y Roginskaya
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Shrabani Basu
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yudong Wang
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bennett Van Houten
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Al-Walid Mohsen
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jerry Vockley
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
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Llanos-González E, Henares-Chavarino ÁA, Pedrero-Prieto CM, García-Carpintero S, Frontiñán-Rubio J, Sancho-Bielsa FJ, Alcain FJ, Peinado JR, Rabanal-Ruíz Y, Durán-Prado M. Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer's Disease. Front Neurosci 2020; 13:1444. [PMID: 32063825 PMCID: PMC7000623 DOI: 10.3389/fnins.2019.01444] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/24/2019] [Indexed: 12/14/2022] Open
Abstract
Although the basis of Alzheimer’s disease (AD) etiology remains unknown, oxidative stress (OS) has been recognized as a prodromal factor associated to its progression. OS refers to an imbalance between oxidant and antioxidant systems, which usually consist in an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which overwhelms the intrinsic antioxidant defenses. Due to this increased production of ROS and RNS, several biological functions such as glucose metabolism or synaptic activity are impaired. In AD, growing evidence links the ROS-mediated damages with molecular targets including mitochondrial dynamics and function, protein quality control system, and autophagic pathways, affecting the proteostasis balance. In this scenario, OS should be considered as not only a major feature in the pathophysiology of AD but also a potential target to combat the progression of the disease. In this review, we will discuss the role of OS in mitochondrial dysfunction, protein quality control systems, and autophagy associated to AD and suggest innovative therapeutic strategies based on a better understanding of the role of OS and proteostasis.
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Affiliation(s)
- Emilio Llanos-González
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | | | - Cristina María Pedrero-Prieto
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Sonia García-Carpintero
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Javier Frontiñán-Rubio
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Francisco Javier Sancho-Bielsa
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Francisco Javier Alcain
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Juan Ramón Peinado
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Yoana Rabanal-Ruíz
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
| | - Mario Durán-Prado
- Department of Medical Sciences, Faculty of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain.,Oxidative Stress and Neurodegeneration Group, Regional Centre for Biomedical Research, University of Castilla-La Mancha, Ciudad Real, Spain
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3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum–Mitochondria Crosstalk in Rat Brain. Neurotox Res 2019; 37:314-325. [PMID: 31721046 DOI: 10.1007/s12640-019-00122-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 07/21/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a neurometabolic disorder characterized by predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in tissues and biological fluids. Patients often present in the first year of life with metabolic acidosis, non-ketotic hypoglycemia, hypotonia, lethargy, and coma. Since neurological symptoms may be triggered or worsened during episodes of metabolic decompensation, which are characterized by high urinary excretion of organic acids, this study investigated the effects of HMG intracerebroventricular administration on redox homeostasis, citric acid cycle enzyme activities, dynamics (mitochondrial fusion and fission), and endoplasmic reticulum (ER)-mitochondria crosstalk in the brain of neonatal rats euthanized 1 (short term) or 20 days (long term) after injection. HMG induced lipid peroxidation and decreased the activities of glutathione peroxidase (GPx) and citric acid cycle enzymes, suggesting bioenergetic and redox disruption, 1 day after administration. Levels of VDAC1, Grp75, and mitofusin-1, proteins involved in ER-mitochondria crosstalk and mitochondrial fusion, were increased by HMG. Furthermore, HMG diminished synaptophysin levels and tau phosphorylation, and increased active caspase-3 content, indicative of cell damage. Finally, HMG decreased GPx activity and synaptophysin levels, and changed MAPK phosphorylation 20 days after injection, suggesting that long-term toxicity is further induced by this organic acid. Taken together, these data show that HMG induces oxidative stress and disrupts bioenergetics, dynamics, ER-mitochondria communication, and signaling pathways in the brain of rats soon after birth. It may be presumed that these mechanisms underlie the onset and progression of symptoms during decompensation occurring in HL-deficient patients during the neonatal period.
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Ietta F, Valacchi G, Benincasa L, Pecorelli A, Cresti L, Maioli E. Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells. Biofactors 2019; 45:920-929. [PMID: 31408224 DOI: 10.1002/biof.1551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 07/19/2019] [Indexed: 01/22/2023]
Abstract
Rottlerin is a cytostatic and cytotoxic drug in a variety of cancer cells. Our previous experience demonstrated that depending upon the genetic/biochemical background of cancer cells, rottlerin is able to induce both apoptotic and autophagic cell death, or dramatically disturb protein homeostasis leading to lethal cellular atrophy. In the current study, we investigated the cytotoxic effects and mechanisms of rottlerin against human amelanotic A375 melanoma cells. In this cell line, rottlerin exhibits its main and newest cytotoxic properties, that is, growth arrest, apoptosis induction, and translation shutoff. In fact, the drug, time-, and dose-dependently, markedly inhibited cell proliferation through cyclin D1 downregulation and induced apoptotic cell death as early as after 18 h treatment. Mechanistically, rottlerin triggered apoptosis by both intrinsic and extrinsic pathways. Both pathways are likely activated by the downregulation of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein, which simultaneously affects mitochondrial and endoplasmic reticulum (ER) membranes stability. Concomitantly to extrinsic apoptosis induction, the rottlerin-activated ER stress/eukaryotic initiation factor 2 (eIF2) α axis blocked the translational apparatus. The altered proteostasis precluded the complete cells' rescue from death in the presence of apoptosis inhibitors.
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Affiliation(s)
- Francesca Ietta
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Giuseppe Valacchi
- Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy
- NC State University, Plants for Human Health Institute, Kannapolis, North Carolina
- Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea
| | - Linda Benincasa
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Alessandra Pecorelli
- NC State University, Plants for Human Health Institute, Kannapolis, North Carolina
| | - Laura Cresti
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Emanuela Maioli
- Department of Life Sciences, University of Siena, Siena, Italy
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2-Aminoadipic acid (2-AAA) as a potential biomarker for insulin resistance in childhood obesity. Sci Rep 2019; 9:13610. [PMID: 31541119 PMCID: PMC6754510 DOI: 10.1038/s41598-019-49578-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 08/23/2019] [Indexed: 01/09/2023] Open
Abstract
Insulin resistance is an important clinical feature of metabolic syndrome, which includes obesity and type 2 diabetes. Increased adipose energy storage in obesity promote insulin resistance and other metabolic adverse effects. To identify a new link between adipocyte and insulin resistance, we performed targeted metabolite profiling of differentiated adipocytes and studied the association between adipogenic metabolites and insulin resistance. We found a correlation between 2-aminoadipic acid (2-AAA) and adipogenic differentiation. Also, circulatory 2-AAA was positively associated with obesity-related factors (fat mass, fat percent, waist circumference, BMI, BMI z-score, triglycerides, insulin, and HOMA-IR) at baseline and after 2 years in the children cohort study. Of these factors, increased BMI z-score and HOMA-IR were the primary independent factors associated with higher 2-AAA levels, and the baseline 2-AAA level was an indicator of the BMI z-score after 2 years. To validate the relationship between 2-AAA and obesity-related factors, we analyzed changes in 2-AAA levels following obesity intervention programs in two independent studies. In both studies, changes in 2-AAA levels during the intervention period were positively correlated with changes in the BMI z-score and HOMA-IR after adjusting for confounders. Moreover, the 2-AAA levels were increased in cell and mouse models of obesity-related insulin resistance. Excess 2-AAA levels led to impaired insulin signaling in insulin-sensitive cells (liver, skeletal muscle and adipose cells) and caused abnormal gluconeogenesis. Our results demonstrate that 2-AAA is associated with adipogenesis and insulin resistance. In this regard, 2-AAA could be a potential biomarker of obesity and obesity-related metabolic disorders.
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39
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Grings M, Seminotti B, Karunanidhi A, Ghaloul-Gonzalez L, Mohsen AW, Wipf P, Palmfeldt J, Vockley J, Leipnitz G. ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts. Sci Rep 2019; 9:12651. [PMID: 31477743 PMCID: PMC6718683 DOI: 10.1038/s41598-019-49014-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 08/14/2019] [Indexed: 01/21/2023] Open
Abstract
Ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) deficiencies are hereditary disorders that affect the catabolism of sulfur-containing amino acids. ETHE1 deficiency is caused by mutations in the ETHE1 gene, while MoCo deficiency is due to mutations in one of three genes involved in MoCo biosynthesis (MOCS1, MOCS2 and GPHN). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical findings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fibroblasts from four patients with ETHE1 deficiency and one with MOCS1 deficiency. The effect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identified in the same cells, while variable alterations in mitochondrial fusion and fission were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 deficiencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.
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Affiliation(s)
- Mateus Grings
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil. .,Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.
| | - Bianca Seminotti
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.,Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Anuradha Karunanidhi
- Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Lina Ghaloul-Gonzalez
- Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Al-Walid Mohsen
- Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Peter Wipf
- Departments of Chemistry, Pharmaceutical Sciences and Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Johan Palmfeldt
- Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby, Denmark
| | - Jerry Vockley
- Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil. .,Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. .,Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
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40
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IDH2 deficiency exacerbates acetaminophen hepatotoxicity in mice via mitochondrial dysfunction-induced apoptosis. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2333-2341. [DOI: 10.1016/j.bbadis.2019.05.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 12/20/2022]
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Morais Mewes J, Rodrigues Silva Gasparin F, Yoshida T, Amâncio Daniel da Silva M, Raquel Marçal Natali M, Francisco Veiga Bizerra P, Sayuri Utsunomiya K, Hideo Gilglioni E, Shigueaki Mito M, Cristiane Mantovanelli G, Thais Lima de Souza B, Makiyama Klosowski E, Luiza Ishii-Iwamoto E, Constantin J, Polimeni Constantin R. The Role of Mitochondria in Sex-Dependent Differences in Hepatic Steatosis and Oxidative Stress in Response to Cafeteria Diet-Induced Obesity in Mice. Nutrients 2019; 11:E1618. [PMID: 31315289 PMCID: PMC6682896 DOI: 10.3390/nu11071618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/03/2019] [Accepted: 07/11/2019] [Indexed: 12/30/2022] Open
Abstract
Female mice fed a cafeteria diet (FCaf) develop higher liver steatosis and oxidative stress than males (MCaf) as a consequence of unresolved ER stress. Here, we investigated whether mitochondria play a role in this sex difference. The isolated mitochondria from FCaf showed more signs of oxidative stress than those of MCaf, correlated with a reduced content of GSH, increased amount of reactive oxygen species (ROS), and lower activities of enzymes involved in ROS neutralisation. Mitochondria from FCaf and MCaf livers exhibited lower rates of succinate-driven state III respiration and reduced ATPase activity in intact coupled mitochondria compared to their controls fed a standard diet (FC and MC), with no differences between the sexes. Fatty acid oxidation in mitochondria and peroxisomes was higher in MCaf and FCaf compared to their respective controls. In the intact perfused liver, there was no difference between sex or diet regarding the fatty acid oxidation rate. These results indicated that cafeteria diet did not affect mitochondrial energy metabolism, even in FCaf livers, which have higher steatosis and cellular oxidative stress. Nevertheless, the increase in mitochondrial ROS generation associated with a decrease in the antioxidant defence capacity, probably contributes to inducing or reinforcing the ER stress in FCaf livers.
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Affiliation(s)
- Juliana Morais Mewes
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Fabiana Rodrigues Silva Gasparin
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Tiago Yoshida
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Mariana Amâncio Daniel da Silva
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Maria Raquel Marçal Natali
- Department of Morphophysiological Sciences, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Paulo Francisco Veiga Bizerra
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Karina Sayuri Utsunomiya
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Eduardo Hideo Gilglioni
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Marcio Shigueaki Mito
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Gislaine Cristiane Mantovanelli
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Byanca Thais Lima de Souza
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Eduardo Makiyama Klosowski
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Emy Luiza Ishii-Iwamoto
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Jorgete Constantin
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil
| | - Rodrigo Polimeni Constantin
- Department of Biochemistry, Laboratory of Biological Oxidations and Laboratory of Experimental Steatosis, State University of Maringá, Maringá 87020-900, Paraná, Brazil.
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Pinti MV, Fink GK, Hathaway QA, Durr AJ, Kunovac A, Hollander JM. Mitochondrial dysfunction in type 2 diabetes mellitus: an organ-based analysis. Am J Physiol Endocrinol Metab 2019; 316:E268-E285. [PMID: 30601700 PMCID: PMC6397358 DOI: 10.1152/ajpendo.00314.2018] [Citation(s) in RCA: 246] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/27/2018] [Accepted: 12/19/2018] [Indexed: 12/20/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a systemic disease characterized by hyperglycemia, hyperlipidemia, and organismic insulin resistance. This pathological shift in both circulating fuel levels and energy substrate utilization by central and peripheral tissues contributes to mitochondrial dysfunction across organ systems. The mitochondrion lies at the intersection of critical cellular pathways such as energy substrate metabolism, reactive oxygen species (ROS) generation, and apoptosis. It is the disequilibrium of these processes in T2DM that results in downstream deficits in vital functions, including hepatocyte metabolism, cardiac output, skeletal muscle contraction, β-cell insulin production, and neuronal health. Although mitochondria are known to be susceptible to a variety of genetic and environmental insults, the accumulation of mitochondrial DNA (mtDNA) mutations and mtDNA copy number depletion is helping to explain the prevalence of mitochondrial-related diseases such as T2DM. Recent work has uncovered novel mitochondrial biology implicated in disease progressions such as mtDNA heteroplasmy, noncoding RNA (ncRNA), epigenetic modification of the mitochondrial genome, and epitranscriptomic regulation of the mtDNA-encoded mitochondrial transcriptome. The goal of this review is to highlight mitochondrial dysfunction observed throughout major organ systems in the context of T2DM and to present new ideas for future research directions based on novel experimental and technological innovations in mitochondrial biology. Finally, the field of mitochondria-targeted therapeutics is discussed, with an emphasis on novel therapeutic strategies to restore mitochondrial homeostasis in the setting of T2DM.
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Affiliation(s)
- Mark V Pinti
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
- West Virginia University School of Pharmacy , Morgantown, West Virginia
| | - Garrett K Fink
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Quincy A Hathaway
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
- Toxicology Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Andrya J Durr
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Amina Kunovac
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - John M Hollander
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
- Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
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Abstract
Mitochondria undergo continuous challenges in the course of their life, from their generation to their degradation. These challenges include the management of reactive oxygen species, the proper assembly of mitochondrial respiratory complexes and the need to balance potential mutations in the mitochondrial DNA. The detection of damage and the ability to keep it under control is critical to fine-tune mitochondrial function to the organismal energy needs. In this review, we will analyze the multiple mechanisms that safeguard mitochondrial function in light of in crescendo damage. This sequence of events will include initial defense against excessive reactive oxygen species production, compensation mechanisms by the unfolded protein response (UPRmt), mitochondrial dynamics and elimination by mitophagy.
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Affiliation(s)
- Miriam Valera-Alberni
- Nestlé Institute of Health Sciences (NIHS), EPFL Innovation Park, 1015 Lausanne.,School of Life Sciences, EPFL, 1015 Lausanne
| | - Carles Canto
- Nestlé Institute of Health Sciences (NIHS), EPFL Innovation Park, 1015 Lausanne.,School of Life Sciences, EPFL, 1015 Lausanne
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44
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Omura T, Sasaoka M, Hashimoto G, Imai S, Yamamoto J, Sato Y, Nakagawa S, Yonezawa A, Nakagawa T, Yano I, Tasaki Y, Matsubara K. Oxicam-derived non-steroidal anti-inflammatory drugs suppress 1-methyl-4-phenyl pyridinium-induced cell death via repression of endoplasmic reticulum stress response and mitochondrial dysfunction in SH-SY5Y cells. Biochem Biophys Res Commun 2018; 503:2963-2969. [DOI: 10.1016/j.bbrc.2018.08.078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 08/08/2018] [Indexed: 10/28/2022]
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45
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Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling. Exp Cell Res 2018; 370:312-321. [DOI: 10.1016/j.yexcr.2018.06.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 06/23/2018] [Accepted: 06/27/2018] [Indexed: 12/15/2022]
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46
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Abstract
The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3-5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity. Mitochondrial function emerges as a key player in cell fate decisions and in coordinating cellular metabolism, immunity, stress responses and apoptosis. Mediators of mitochondrial signalling include molecules such as ATP and reactive oxygen species and interrelate with pathways such as the mitochondrial unfolded protein response (MT-UPR) and AMP kinase signalling, in turn affecting cell cycle progression and stemness. Alterations in mitochondrial function and MT-UPR activation are integral aspects of pathologies, including IBD and cancer. Mitochondrial signalling and concomitant changes in metabolism contribute to intestinal homeostasis and regulate IEC dedifferentiation-differentiation programmes in the context of diseases, suggesting that mitochondrial function as a cellular checkpoint critically contributes to disease outcome. This Review highlights mitochondrial function and MT-UPR signalling in epithelial cell stemness, differentiation and lineage commitment and illustrates mitochondrial function in intestinal diseases.
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47
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Wang X, Du H, Shao S, Bo T, Yu C, Chen W, Zhao L, Li Q, Wang L, Liu X, Su X, Sun M, Song Y, Gao L, Zhao J. Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis. Hepatology 2018; 68:62-77. [PMID: 29356058 DOI: 10.1002/hep.29788] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/08/2017] [Accepted: 01/12/2018] [Indexed: 01/04/2023]
Abstract
Physiological opening of the mitochondrial permeability transition pore (mPTP) is indispensable for maintaining mitochondrial function and cell homeostasis, but the role of the mPTP and its initial factor, cyclophilin D (CypD), in hepatic steatosis is unclear. Here, we demonstrate that excess mPTP opening is mediated by an increase of CypD expression induced hepatic mitochondrial dysfunction. Notably, such mitochondrial perturbation occurred before detectable triglyceride accumulation in the liver of high-fat diet-fed mice. Moreover, either genetic knockout or pharmacological inhibition of CypD could ameliorate mitochondrial dysfunction, including excess mPTP opening and stress, and down-regulate the transcription of sterol regulatory element-binding protein-1c, a key factor of lipogenesis. In contrast, the hepatic steatosis in adenoviral overexpression of CypD-infected mice was aggravated relative to the control group. Blocking p38 mitogen-activated protein kinase or liver-specific Ire1α knockout could resist CypD-induced sterol regulatory element-binding protein-1c expression and steatosis. Importantly, CypD inhibitor applied prior to or after the onset of triglyceride deposition substantially prevented or ameliorated fatty liver. CONCLUSION CypD stimulates mPTP excessive opening, subsequently causing endoplasmic reticulum stress through p38 mitogen-activated protein kinase activation, and results in enhanced sterol regulatory element-binding protein-1c transcription and hepatic steatosis. (Hepatology 2018;68:62-77).
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Affiliation(s)
- Xiaolei Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Heng Du
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX
| | - Shanshan Shao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Tao Bo
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Chunxiao Yu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Wenbin Chen
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Lifang Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Qiu Li
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Li Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Department of Physiology and Neurobiology and the Institute for Systems Genomics, University of Connecticut, Storrs, CT
| | - Xiaojing Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Xiaohui Su
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Mingqi Sun
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Yongfeng Song
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
| | - Ling Gao
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
- Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, China
- Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China
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48
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Protection by different classes of dietary polyphenols against palmitic acid-induced steatosis, nitro-oxidative stress and endoplasmic reticulum stress in HepG2 hepatocytes. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.02.033] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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49
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Rieusset J. The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update. Cell Death Dis 2018. [PMID: 29523782 PMCID: PMC5844895 DOI: 10.1038/s41419-018-0416-1] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The contact sites that the endoplasmic reticulum (ER) forms with mitochondria, called mitochondria-associated membranes (MAMs), are a hot topic in biological research, and both their molecular determinants and their numerous roles in several signaling pathways are is continuously evolving. MAMs allow the exchange between both organelles of lipids, calcium (Ca2+), and likely reactive oxygen species, allowing adaptations of both cellular bioenergetics and cell fate depending of cellular needs or stresses. Therefore, it is not surprising that MAMs affect cellular metabolism. Nevertheless, recent arguments suggest that MAMs could also act as key hub of hormonal and/or nutrient signaling in several insulin-sensitive tissues, pointing a specific role of MAMs in the control of glucose homeostasis. Here, I provide a brief review and update on current key signaling roles of the MAMs in the control of glucose homeostasis in both health and metabolic diseases. Particularly, the relevance of ER-mitochondria miscommunication in the disruption of glucose homeostasis is analyzed in details in the liver, skeletal muscle, adipose tissue, and beta cells of the pancreas.
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Affiliation(s)
- Jennifer Rieusset
- Laboratoire CarMeN, Unité Mixte de Recherche INSERM U-1060 et INRA U-1397, Université Lyon 1, Oullins, 69600, France.
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50
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Leipnitz G, Mohsen AW, Karunanidhi A, Seminotti B, Roginskaya VY, Markantone DM, Grings M, Mihalik SJ, Wipf P, Van Houten B, Vockley J. Evaluation of mitochondrial bioenergetics, dynamics, endoplasmic reticulum-mitochondria crosstalk, and reactive oxygen species in fibroblasts from patients with complex I deficiency. Sci Rep 2018; 8:1165. [PMID: 29348607 PMCID: PMC5773529 DOI: 10.1038/s41598-018-19543-3] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 01/03/2018] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial complex I (CI) deficiency is the most frequent cause of oxidative phosphorylation (OXPHOS) disorders in humans. In order to benchmark the effects of CI deficiency on mitochondrial bioenergetics and dynamics, respiratory chain (RC) and endoplasmic reticulum (ER)-mitochondria communication, and superoxide production, fibroblasts from patients with mutations in the ND6, NDUFV1 or ACAD9 genes were analyzed. Fatty acid metabolism, basal and maximal respiration, mitochondrial membrane potential, and ATP levels were decreased. Changes in proteins involved in mitochondrial dynamics were detected in various combinations in each cell line, while variable changes in RC components were observed. ACAD9 deficient cells exhibited an increase in RC complex subunits and DDIT3, an ER stress marker. The level of proteins involved in ER-mitochondria communication was decreased in ND6 and ACAD9 deficient cells. |ΔΨ| and cell viability were further decreased in all cell lines. These findings suggest that disruption of mitochondrial bioenergetics and dynamics, ER-mitochondria crosstalk, and increased superoxide contribute to the pathophysiology in patients with ACAD9 deficiency. Furthermore, treatment of ACAD9 deficient cells with JP4-039, a novel mitochondria-targeted reactive oxygen species, electron and radical scavenger, decreased superoxide level and increased basal and maximal respiratory rate, identifying a potential therapeutic intervention opportunity in CI deficiency.
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Affiliation(s)
- Guilhian Leipnitz
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.,Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
| | - Al-Walid Mohsen
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Anuradha Karunanidhi
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Bianca Seminotti
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Vera Y Roginskaya
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Desiree M Markantone
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Mateus Grings
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.,Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil
| | - Stephanie J Mihalik
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Bennett Van Houten
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Jerry Vockley
- Division Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. .,Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
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