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Sheth AI, Althoff MJ, Tolison H, Engel K, Amaya ML, Krug AE, Young TN, Minhajuddin M, Pei S, Patel SB, Winters A, Miller R, Shelton IT, St-Germain J, Ling T, Jones CL, Raught B, Gillen AE, Ransom M, Staggs S, Smith CA, Pollyea DA, Stevens BM, Jordan CT. Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium. Cancer Discov 2024; 14:1922-1939. [PMID: 38787341 PMCID: PMC11452272 DOI: 10.1158/2159-8290.cd-23-1145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 04/19/2024] [Accepted: 05/22/2024] [Indexed: 05/25/2024]
Abstract
Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.
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Affiliation(s)
- Anagha Inguva Sheth
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark J Althoff
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
- These authors contributed equally
| | - Hunter Tolison
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
- These authors contributed equally
| | - Krysta Engel
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Maria L. Amaya
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Anna E. Krug
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Tracy N. Young
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mohammad Minhajuddin
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Shanshan Pei
- Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine
| | - Sweta B. Patel
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Amanda Winters
- Division of Pediatric Hematology and Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Regan Miller
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ian T. Shelton
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jonathan St-Germain
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Tianyi Ling
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Courtney L. Jones
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center; Cincinnati, OH, USA
| | - Brian Raught
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Austin E. Gillen
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Monica Ransom
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sarah Staggs
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Clayton A. Smith
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Daniel A. Pollyea
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Brett M. Stevens
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Craig T. Jordan
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
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Danylovych HV, Danylovych YV, Pavliuk MR, Kosterin SO. Products of oxidative and non-oxidative metabolism of L-arginine as potential regulators of Ca 2+ transport in mitochondria of uterine smooth muscle. Biochim Biophys Acta Gen Subj 2024; 1868:130652. [PMID: 38857773 DOI: 10.1016/j.bbagen.2024.130652] [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: 03/14/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Mitochondria play a crucial role in maintaining Ca2+ homeostasis in cells. Due to the critical regulatory role of the products of oxidative and non-oxidative metabolism of L-arginine, it is essential to clarify their effect on Ca2+ transport in smooth muscle mitochondria. Experiments were performed on the uterine myocytes of rats and isolated mitochondria. The possibility of NO synthesis by mitochondria was demonstrated by confocal microscopy and spectrofluorimetry methods using the NO-sensitive fluorescent probe DAF-FM and Mitotracker Orange CM-H2TMRos. It was shown that 50 μM L-arginine stimulates the energy-dependent accumulation of Ca2+ in mitochondria using the fluorescent probe Fluo-4 AM. A similar effect occurred when using nitric oxide donors 100 μM SNP, SNAP, and sodium nitrite (SN) directly. The stimulating effect was eliminated in the presence of the NO scavenger C-PTIO. Nitric oxide reduces the electrical potential in mitochondria without causing them to swell. The stimulatory effect of spermine on the accumulation of Ca2+ by mitochondria is attributed to the enhancement of NO synthesis, which was demonstrated with the use of C-PTIO, NO-synthase inhibitors (100 μM NA and L-NAME), as well as by direct monitoring of NO synthesis fluorescent probe DAF-FM. A conclusion was drawn about the potential regulatory effect of the product of the oxidative metabolism of L-arginine - NO on the transport of Ca2+ in the mitochondria of the myometrium, as well as the corresponding effect of the product of non-oxidative metabolism -spermine by increasing the synthesis of NO in these subcellular structures.
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Affiliation(s)
- Hanna V Danylovych
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
| | - Yuriy V Danylovych
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Maksym R Pavliuk
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
| | - Sergiy O Kosterin
- Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
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3
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Kunnas K, Vihinen-Ranta M, Leclerc S. Progression of herpesvirus infection is inhibited by calcium reporter. MICROPUBLICATION BIOLOGY 2024; 2024:10.17912/micropub.biology.001269. [PMID: 39228992 PMCID: PMC11369692 DOI: 10.17912/micropub.biology.001269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/16/2024] [Accepted: 08/16/2024] [Indexed: 09/05/2024]
Abstract
During infection, Herpes simplex virus type 1 (HSV-1) alters the mitochondrial structure and function of the host cell. Live-cell imaging with fluorescent reporters revealed increased mitochondrial calcium and a transient ROS enrichment after HSV-1 infection. Notably, cells co-transfected with a calcium reporter displayed smaller viral replication compartments, while those with a ROS reporter exhibited average growth of viral replication compartments. Our findings suggest that the virus-induced increase in mitochondrial calcium, followed by an increased amount of bound calcium reporter, interferes with the progression of the infection.
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Affiliation(s)
- Kari Kunnas
- Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyvaskyla, Central Finland, Finland
| | - Maija Vihinen-Ranta
- Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyvaskyla, Central Finland, Finland
| | - Simon Leclerc
- Department of Biological and Environmental Science and Nanoscience Center, University of Jyväskylä, Jyvaskyla, Central Finland, Finland
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4
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Chen M, Feng S, Lv H, Wang Z, Zeng Y, Shao C, Lin W, Zhang Z. OsCIPK2 mediated rice root microorganisms and metabolites to improve plant nitrogen uptake. BMC PLANT BIOLOGY 2024; 24:285. [PMID: 38627617 PMCID: PMC11020999 DOI: 10.1186/s12870-024-04982-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 04/03/2024] [Indexed: 04/19/2024]
Abstract
Crop roots are colonized by large numbers of microorganisms, collectively known as the root-microbiome, which modulate plant growth, development and contribute to elemental nutrient uptake. In conditions of nitrogen limitation, the over-expressed Calcineurin B-like interacting protein kinase 2 (OsCIPK2) gene with root-specific promoter (RC) has been shown to enhance growth and nitrogen uptake in rice. Analysis of root-associated bacteria through high-throughput sequencing revealed that OsCIPK2 has a significant impact on the diversity of the root microbial community under low nitrogen stress. The quantification of nifH gene expression demonstrated a significant enhancement in nitrogen-fixing capabilities in the roots of RC transgenetic rice. Synthetic microbial communities (SynCom) consisting of six nitrogen-fixing bacterial strains were observed to be enriched in the roots of RC, leading to a substantial improvement in rice growth and nitrogen uptake in nitrogen-deficient soils. Forty and twenty-three metabolites exhibiting differential abundance were identified in the roots and rhizosphere soils of RC transgenic rice compared to wild-type (WT) rice. These findings suggest that OSCIPK2 plays a role in restructuring the microbial community in the roots through the regulation of metabolite synthesis and secretion. Further experiments involving the exogenous addition of citric acid revealed that an optimal concentration of this compound facilitated the growth of nitrogen-fixing bacteria and substantially augmented their population in the soil, highlighting the importance of citric acid in promoting nitrogen fixation under conditions of low nitrogen availability. These findings suggest that OsCIPK2 plays a role in enhancing nitrogen uptake by rice plants from the soil by influencing the assembly of root microbial communities, thereby offering valuable insights for enhancing nitrogen utilization in rice cultivation.
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Affiliation(s)
- Mengying Chen
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
| | - Shizhong Feng
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
- Fujian Provincial Key Laboratory of Agroecological Processing and Safety Monitoring, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - He Lv
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
| | - Zewen Wang
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
| | - Yuhang Zeng
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
| | - Caihong Shao
- Soil and Fertilizer & Resources and Environment Institute, Jiangxi Academy of Agricultural Sciences, Nanchang, 330200, China
| | - Wenxiong Lin
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China
- Fujian Provincial Key Laboratory of Agroecological Processing and Safety Monitoring, Fujian Agriculture and Forestry University, Fuzhou, 350002, China
| | - Zhixing Zhang
- College of JunCao Science and Ecology, Fujian Agricultural and Forestry University, Fuzhou, Fujian, 350002, China.
- Key Laboratory of Crop Ecology and Molecular Physiology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, 350002, China.
- Fujian Provincial Key Laboratory of Agroecological Processing and Safety Monitoring, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
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5
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Hinton A, Katti P, Mungai M, Hall DD, Koval O, Shao J, Vue Z, Lopez EG, Rostami R, Neikirk K, Ponce J, Streeter J, Schickling B, Bacevac S, Grueter C, Marshall A, Beasley HK, Do Koo Y, Bodine SC, Nava NGR, Quintana AM, Song LS, Grumbach I, Pereira RO, Glancy B, Abel ED. ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle. J Cell Physiol 2024; 239:e31204. [PMID: 38419397 PMCID: PMC11144302 DOI: 10.1002/jcp.31204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/15/2023] [Accepted: 01/16/2024] [Indexed: 03/02/2024]
Abstract
Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.
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Affiliation(s)
- Antentor Hinton
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
| | - Prasanna Katti
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA, 20892
| | - Margaret Mungai
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Duane D. Hall
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
| | - Olha Koval
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Jianqiang Shao
- Central Microscopy Research Facility, Iowa City, IA USA 52242
| | - Zer Vue
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
| | - Edgar Garza Lopez
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
| | - Rahmati Rostami
- Department of Genetic Medicine, Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA, 10065
| | - Kit Neikirk
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
| | - Jessica Ponce
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Jennifer Streeter
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Brandon Schickling
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Department of Medicine, Duke University, Durham, NC, USA 27708
| | - Serif Bacevac
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Chad Grueter
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Andrea Marshall
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
| | - Heather K. Beasley
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232
| | - Young Do Koo
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Sue C. Bodine
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
- Oklahoma Medical Research Foundation, Oklahoma City, OK, USA 73104
| | - Nayeli G. Reyes Nava
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, USA 79968
| | - Anita M. Quintana
- Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, USA 79968
| | - Long-Sheng Song
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Isabella Grumbach
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Renata O. Pereira
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
| | - Brian Glancy
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA, 20892
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA 20892
| | - E. Dale Abel
- Department of Internal Medicine, University of Iowa - Carver College of Medicine, Iowa City, IA, USA 52242
- Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA 52242
- Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA 90095
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Lv Z, Hu J, Huang M, Pan G, Xu G, Yang M. Molecular mechanisms of cadmium-induced cytotoxicity in human ovarian granulosa cells identified using integrated omics. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 272:116026. [PMID: 38290317 DOI: 10.1016/j.ecoenv.2024.116026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/01/2024]
Abstract
Epidemiological and clinical data have demonstrated that exposure to cadmium (Cd), a toxic heavy metal, is associated with an increased risk of female infertility. Granulosa cells, the main somatic cells comprising ovarian follicles, are one of the main targets of Cd in the ovaries. However, the mechanism by which Cd induces cytotoxicity in granulosa cells has not been fully elucidated. In this study, we exposed human ovarian granulosa cells (KGN cells) to Cd and conducted in vitro cell experiments and multi-omics (metabolomics and transcriptomics) methods to elucidate these mechanisms. Cd exposure was found to not only induce the apoptosis of the KGN cells but also further reduced mitochondrial function by decreasing mitochondrial membrane potential, ATP production, and respiratory chain complex activity as well as increasing mitochondrial reactive oxygen species (ROS) production. A total of 443 differentially expressed metabolites (160 upregulated and 283 downregulated) and 5200 differentially expressed genes (4634 upregulated and 566 downregulated) were observed in the Cd exposed-cells. The multi-omics data showed that Cd interfered with citric acid cycle (TCA cycle), amino acid (including alanine, glycine, serine, threonine, arginine, and proline) metabolism, and calcium signaling. These findings help to better elucidate the potential toxicity mechanisms of Cd on granulosa cells and the ovary.
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Affiliation(s)
- Zili Lv
- School of Medical and Life Sciences/Reproductive & Women-Children Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu 610041, China
| | - Jun Hu
- Sichuan Treatment Center for Gynaecologic and Breast Diseases (Gynaecology), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Mingquan Huang
- Sichuan Treatment Center for Gynaecologic and Breast Diseases (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Guangrui Pan
- Sichuan Treatment Center for Gynaecologic and Breast Diseases (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Guofeng Xu
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Meng Yang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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7
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Feng W, Kao TC, Jiang J, Zeng X, Chen S, Zeng J, Chen Y, Ma X. The dynamic equilibrium between the protective and toxic effects of matrine in the development of liver injury: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1315584. [PMID: 38348397 PMCID: PMC10859759 DOI: 10.3389/fphar.2024.1315584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024] Open
Abstract
Background: Matrine, an alkaloid derived from the dried roots of Sophora flavescens Aiton, has been utilized for the treatment of liver diseases, but its potential hepatotoxicity raises concerns. However, the precise condition and mechanism of action of matrine on the liver remain inconclusive. Therefore, the objective of this systematic review and meta-analysis is to comprehensively evaluate both the hepatoprotective and hepatotoxic effects of matrine and provide therapeutic guidance based on the findings. Methods: The meta-analysis systematically searched relevant preclinical literature up to May 2023 from eight databases, including PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, WanFang Med Online, China Science and Technology Journal Database, and China Biomedical Literature Service System. The CAMARADES system assessed the quality and bias of the evidence. Statistical analysis was conducted using STATA, which included the use of 3D maps and radar charts to display the effects of matrine dosage and frequency on hepatoprotection and hepatotoxicity. Results: After a thorough screening, 24 studies involving 657 rodents were selected for inclusion. The results demonstrate that matrine has bidirectional effects on ALT and AST levels, and it also regulates SOD, MDA, serum TG, serum TC, IL-6, TNF-α, and CAT levels. Based on our comprehensive three-dimensional analysis, the optimal bidirectional effective dosage of matrine ranges from 10 to 69.1 mg/kg. However, at a dose of 20-30 mg/kg/d for 0.02-0.86 weeks, it demonstrated high liver protection and low toxicity. The molecular docking analysis revealed the interaction between MT and SERCA as well as SREBP-SCAP complexes. Matrine could alter Ca2+ homeostasis in liver injury via multiple pathways, including the SREBP1c/SCAP, Notch/RBP-J/HES1, IκK/NF-κB, and Cul3/Rbx1/Keap1/Nrf2. Conclusion: Matrine has bidirectional effects on the liver at doses ranging from 10 to 69.1 mg/kg by influencing Ca2+ homeostasis in the cytoplasm, endoplasmic reticulum, Golgi apparatus, and mitochondria. Systematic review registration: https://inplasy.com/, identifier INPLASY202340114.
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Affiliation(s)
- Weiyi Feng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Te-chan Kao
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiajie Jiang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shuang Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Chen
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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8
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Haynes V, Giulivi C. Calcium-Dependent Interaction of Nitric Oxide Synthase with Cytochrome c Oxidase: Implications for Brain Bioenergetics. Brain Sci 2023; 13:1534. [PMID: 38002494 PMCID: PMC10669843 DOI: 10.3390/brainsci13111534] [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: 09/19/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Targeted nitric oxide production is relevant for maintaining cellular energy production, protecting against oxidative stress, regulating cell death, and promoting neuroprotection. This study aimed to characterize the putative interaction of nitric-oxide synthase with mitochondrial proteins. The primary finding of this study is that cytochrome c oxidase (CCO) subunit IV (CCOIV) is associated directly with NOS in brain mitochondria when calcium ions are present. The matrix side of CCOIV binds to the N-terminus of NOS, supported by the abrogation of the binding by antibodies towards the N-terminus of NOS. Evidence supporting the interaction between CCOIV and NOS was provided by the coimmunoprecipitation of NOS from detergent-solubilized whole rat brain mitochondria with antibodies to CCOIV and the coimmunoprecipitation of CCOIV from crude brain NOS preparations using antibodies to NOS. The CCOIV domain that interacts with NOS was identified using a series of overlapping peptides derived from the primary sequence of CCOIV. As calcium ions not only activate NOS, but also facilitate the docking of NOS to CCOIV, this study points to a dynamic mechanism of controlling the bioenergetics by calcium changes, thereby adapting bioenergetics to cellular demands.
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Affiliation(s)
- Virginia Haynes
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
| | - Cecilia Giulivi
- School of Veterinary Medicine, Department Molecular Biosciences, University of California Davis, Davis, CA 95616, USA
- Medical Investigation of Neurodevelopmental Disorders (MIND) Institute UCDH, University of California Davis, Sacramento, CA 95817, USA
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9
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Sheth AI, Engel K, Tolison H, Althoff MJ, Amaya ML, Krug A, Young T, Pei S, Patel SB, Minhajuddin M, Winters A, Miller R, Shelton I, St-Germain J, Ling T, Jones C, Raught B, Gillen A, Ransom M, Staggs S, Smith CA, Pollyea DA, Stevens BM, Jordan CT. Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560330. [PMID: 37873284 PMCID: PMC10592899 DOI: 10.1101/2023.10.02.560330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.
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Affiliation(s)
- Anagha Inguva Sheth
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Krysta Engel
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
- These authors contributed equally
| | - Hunter Tolison
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
- These authors contributed equally
| | - Mark J Althoff
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Maria L. Amaya
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Anna Krug
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Tracy Young
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Shanshan Pei
- Liangzhu Laboratory, Zhejiang University Medical Center, Bone Marrow Transplantation Center, Hangzhou, China
| | - Sweta B. Patel
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mohammad Minhajuddin
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Amanda Winters
- Division of Pediatric Hematology and Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Regan Miller
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ian Shelton
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jonathan St-Germain
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Tianyi Ling
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Courtney Jones
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Brian Raught
- Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Austin Gillen
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Monica Ransom
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sarah Staggs
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Clayton A. Smith
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Daniel A. Pollyea
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Brett M. Stevens
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Craig T. Jordan
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA
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10
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Rozenfeld M, Azoulay IS, Ben Kasus Nissim T, Stavsky A, Melamed M, Stutzmann G, Hershfinkel M, Kofman O, Sekler I. Essential role of the mitochondrial Na +/Ca 2+ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning. Cell Rep 2022; 41:111772. [PMID: 36476859 PMCID: PMC10521900 DOI: 10.1016/j.celrep.2022.111772] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 07/06/2022] [Accepted: 11/10/2022] [Indexed: 12/12/2022] Open
Abstract
Impaired phosphodiesterase (PDE) function and mitochondrial Ca2+ (i.e., [Ca2+]m) lead to multiple health syndromes by an unknown pathway. Here, we fluorescently monitor robust [Ca2+]m efflux mediated by the mitochondrial Na+/Ca2+ exchanger NCLX in hippocampal neurons sequentially evoked by caffeine and depolarization. Surprisingly, neuronal depolarization-induced Ca2+ transients alone fail to evoke strong [Ca2+]m efflux in wild-type (WT) neurons. However, pre-treatment with the selective PDE2 inhibitor Bay 60-7550 effectively rescues [Ca2+]m efflux similarly to caffeine. Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site. We find that the protection of neurons against excitotoxic insults, conferred by PDE2 inhibition in WT neurons, is NCLX dependent. Finally, the administration of Bay 60-7550 enhances new object recognition in WT, but not in NCLX knockout (KO), mice. Our results identify a link between PDE and [Ca2+]m signaling that may provide effective therapy for cognitive and ischemic syndromes.
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Affiliation(s)
- Maya Rozenfeld
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ivana Savic Azoulay
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Tsipi Ben Kasus Nissim
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Alexandra Stavsky
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Moran Melamed
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Grace Stutzmann
- Rosalind Franklin University of Medicine and Science, Chicago Medical School, Center for Neurodegenerative Disease and Therapeutics, Chicago, IL, USA
| | - Michal Hershfinkel
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ora Kofman
- Department of Psychology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Israel Sekler
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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11
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Hool LC. Elucidating the role of the L-type calcium channel in excitability and energetics in the heart: The ISHR 2020 Research Achievement Award Lecture. J Mol Cell Cardiol 2022; 172:100-108. [PMID: 36041287 DOI: 10.1016/j.yjmcc.2022.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/31/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022]
Abstract
Cardiovascular disease continues to be the leading health burden worldwide and with the rising rates in obesity and type II diabetes and ongoing effects of long COVID, it is anticipated that the burden of cardiovascular morbidity and mortality will increase. Calcium is essential to cardiac excitation and contraction. The main route for Ca2+ influx is the L-type Ca2+ channel (Cav1.2) and embryos that are homozygous null for the Cav1.2 gene are lethal at day 14 postcoitum. Acute changes in Ca2+ influx through the channel contribute to arrhythmia and sudden death, and chronic increases in intracellular Ca2+ contribute to pathological hypertrophy and heart failure. We use a multidisciplinary approach to study the regulation of the channel from the molecular level through to in vivo CRISPR mutant animal models. Here we describe some examples of our work from over 2 decades studying the role of the channel under physiological and pathological conditions. Our single channel analysis of purified human Cav1.2 protein in proteoliposomes has contributed to understanding direct molecular regulation of the channel including identifying the critical serine involved in the "fight or flight" response. Using the same approach we identified the cysteine responsible for altered function during oxidative stress. Chronic activation of the L-type Ca2+ channel during oxidative stress occurs as a result of persistent glutathionylation of the channel that contributes to the development of hypertrophy. We describe for the first time that activation of the channel alters mitochondrial function (and energetics) on a beat-to-beat basis via movement of cytoskeletal proteins. In translational studies we have used this response to "report" mitochondrial function in models of cardiomyopathy and to test efficacy of novel therapies to prevent cardiomyopathy.
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Affiliation(s)
- Livia C Hool
- School of Human Sciences, University of Western Australia, Crawley, WA, Australia; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia.
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12
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Hong SG, Shin J, Choi SY, Powers JC, Meister BM, Sayoc J, Son JS, Tierney R, Recchia FA, Brown MD, Yang X, Park JY. Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells. JCI Insight 2022; 7:e159286. [PMID: 36134656 PMCID: PMC9514384 DOI: 10.1172/jci.insight.159286] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Endothelial mitochondria play a pivotal role in maintaining endothelial cell (EC) homeostasis through constantly altering their size, shape, and intracellular localization. Studies show that the disruption of the basal mitochondrial network in EC, forming excess fragmented mitochondria, implicates cardiovascular disease. However, cellular consequences underlying the morphological changes in the endothelial mitochondria under distinctively different, but physiologically occurring, flow patterns (i.e., unidirectional flow [UF] versus disturbed flow [DF]) are largely unknown. The purpose of this study was to investigate the effect of different flow patterns on mitochondrial morphology and its implications in EC phenotypes. We show that mitochondrial fragmentation is increased at DF-exposed vessel regions, where elongated mitochondria are predominant in the endothelium of UF-exposed regions. DF increased dynamin-related protein 1 (Drp1), mitochondrial reactive oxygen species (mtROS), hypoxia-inducible factor 1, glycolysis, and EC activation. Inhibition of Drp1 significantly attenuated these phenotypes. Carotid artery ligation and microfluidics experiments further validate that the significant induction of mitochondrial fragmentation was associated with EC activation in a Drp1-dependent manner. Contrarily, UF in vitro or voluntary exercise in vivo significantly decreased mitochondrial fragmentation and enhanced fatty acid uptake and OXPHOS. Our data suggest that flow patterns profoundly change mitochondrial fusion/fission events, and this change contributes to the determination of proinflammatory and metabolic states of ECs.
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Affiliation(s)
- Soon-Gook Hong
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
- Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania, USA
| | - Junchul Shin
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
| | - Soo Young Choi
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
| | | | - Benjamin M. Meister
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
- Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania, USA
| | - Jacqueline Sayoc
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
| | - Jun Seok Son
- Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ryan Tierney
- Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania, USA
| | - Fabio A. Recchia
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
- Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy
| | - Michael D. Brown
- Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryland, USA
| | - Xiaofeng Yang
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
| | - Joon-Young Park
- Cardiovascular Research Center, Lewis Katz School of Medicine, and
- Department of Kinesiology, College of Public Health, Temple University, Philadelphia, Pennsylvania, USA
- Robbins College of Health and Human Sciences, Baylor University, Waco, Texas, USA
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13
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Helwig M, Ulusoy A, Rollar A, O’Sullivan SA, Lee SSL, Aboutalebi H, Pinto-Costa R, Jevans B, Klinkenberg M, Di Monte DA. Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading. SCIENCE ADVANCES 2022; 8:eabn0356. [PMID: 36044566 PMCID: PMC9432848 DOI: 10.1126/sciadv.abn0356] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 07/15/2022] [Indexed: 05/31/2023]
Abstract
Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of α-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated α-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced α-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced α-synuclein spreading.
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Affiliation(s)
- Michael Helwig
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Ayse Ulusoy
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Angela Rollar
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | | | - Shirley S. L. Lee
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Helia Aboutalebi
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Rita Pinto-Costa
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | - Benjamin Jevans
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
| | | | - Donato A. Di Monte
- German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
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14
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Perry RJ. Regulation of Hepatic Lipid and Glucose Metabolism by INSP3R1. Diabetes 2022; 71:1834-1841. [PMID: 35657697 PMCID: PMC9450566 DOI: 10.2337/dbi22-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/13/2022] [Indexed: 11/13/2022]
Abstract
With the rising epidemics of obesity and nonalcoholic fatty liver disease (NAFLD) and its downstream consequences including steatohepatitis, cirrhosis, and type 2 diabetes in the U.S. and worldwide, new therapeutic approaches are urgently needed to treat these devastating conditions. Glucagon, known for a century to be a glucose-raising hormone and clearly demonstrated to contribute to fasting and postprandial hyperglycemia in both type 1 and type 2 diabetes, represents an unlikely target to improve health in those with metabolic syndrome. However, recent work from our group and others' identifies an unexpected role for glucagon as a potential means of treating NAFLD, improving insulin sensitivity, and improving the lipid profile. We propose a unifying, calcium-dependent mechanism for glucagon's effects both to stimulate hepatic gluconeogenesis and to enhance hepatic mitochondrial oxidation: signaling through the inositol 1,4,5-trisphosphate receptor type 1 (INSP3R1), glucagon activates phospholipase C (PKC)/protein kinase A (PKA) signaling to enhance adipose triglyceride lipase (ATGL)-dependent intrahepatic lipolysis and, in turn, increase cytosolic gluconeogenesis by allosteric activation of pyruvate carboxylase. Simultaneously in the mitochondria, calcium transferred through mitochondria-associated membranes activates several dehydrogenases in the tricarboxylic acid cycle, correlated with an increase in mitochondrial energy expenditure and reduction in ectopic lipid. This model suggests that short-term, cyclic treatment with glucagon or other INSP3R1 antagonists could hold promise as a means to reset lipid homeostasis in patients with NAFLD.
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Affiliation(s)
- Rachel J. Perry
- Section of Endocrinology & Metabolism, Department of Internal Medicine, and Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT
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15
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Morciano G, Rimessi A, Patergnani S, Vitto VAM, Danese A, Kahsay A, Palumbo L, Bonora M, Wieckowski MR, Giorgi C, Pinton P. Calcium dysregulation in heart diseases: Targeting calcium channels to achieve a correct calcium homeostasis. Pharmacol Res 2022; 177:106119. [PMID: 35131483 DOI: 10.1016/j.phrs.2022.106119] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 12/16/2022]
Abstract
Intracellular calcium signaling is a universal language source shared by the most part of biological entities inside cells that, all together, give rise to physiological and functional anatomical units, the organ. Although preferentially recognized as signaling between cell life and death processes, in the heart it assumes additional relevance considered the importance of calcium cycling coupled to ATP consumption in excitation-contraction coupling. The concerted action of a plethora of exchangers, channels and pumps inward and outward calcium fluxes where needed, to convert energy and electric impulses in muscle contraction. All this without realizing it, thousands of times, every day. An improper function of those proteins (i.e., variation in expression, mutations onset, dysregulated channeling, differential protein-protein interactions) being part of this signaling network triggers a short circuit with severe acute and chronic pathological consequences reported as arrhythmias, cardiac remodeling, heart failure, reperfusion injury and cardiomyopathies. By acting with chemical, peptide-based and pharmacological modulators of these players, a correction of calcium homeostasis can be achieved accompanied by an amelioration of clinical symptoms. This review will focus on all those defects in calcium homeostasis which occur in the most common cardiac diseases, including myocardial infarction, arrhythmia, hypertrophy, heart failure and cardiomyopathies. This part will be introduced by the state of the art on the proteins involved in calcium homeostasis in cardiomyocytes and followed by the therapeutic treatments that to date, are able to target them and to revert the pathological phenotype.
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Affiliation(s)
- Giampaolo Morciano
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, RA, Italy.
| | - Alessandro Rimessi
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Veronica A M Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Alberto Danese
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Asrat Kahsay
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Laura Palumbo
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Massimo Bonora
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism. Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, RA, Italy.
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16
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do Amaral MA, Paredes LC, Padovani BN, Mendonça-Gomes JM, Montes LF, Câmara NOS, Morales Fénero C. Mitochondrial connections with immune system in Zebrafish. FISH AND SHELLFISH IMMUNOLOGY REPORTS 2021; 2:100019. [PMID: 36420514 PMCID: PMC9680083 DOI: 10.1016/j.fsirep.2021.100019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/12/2021] [Accepted: 08/12/2021] [Indexed: 12/19/2022] Open
Abstract
Mitochondria are organelles commonly associated with adenosine triphosphate (ATP) formation through the oxidative phosphorylation (OXPHOS) process. However, mitochondria are also responsible for functions such as calcium homeostasis, apoptosis, autophagy, and production of reactive oxygen species (ROS) that, in conjunction, can lead to different cell fate decisions. Mitochondrial morphology changes rely on nutrients' availability and the bioenergetics demands of the cells, in a process known as mitochondrial dynamics, which includes both fusion and fission. This organelle senses the microenvironment and can modify the cells to either a pro or anti-inflammatory profile. The zebrafish has been increasingly used to research mitochondrial dynamics and its connection with the immune system since the pathways and molecules involved in these processes are conserved on this fish. Several genetic tools and technologies are currently available to analyze the behavior of mitochondria in zebrafish. However, even though zebrafish presents several similar processes known in mammals, the effect of the mitochondria in the immune system has not been so broadly studied in this model. In this review, we summarize the current knowledge in zebrafish studies regarding mitochondrial function and immuno metabolism.
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Affiliation(s)
- Mariana Abrantes do Amaral
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, SP, Brazil
| | - Lais Cavalieri Paredes
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Barbara Nunes Padovani
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Juliana Moreira Mendonça-Gomes
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Luan Fávero Montes
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Department of Medicine, Federal University of São Paulo, São Paulo, SP, Brazil
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Camila Morales Fénero
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
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17
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Morciano G, Vitto VAM, Bouhamida E, Giorgi C, Pinton P. Mitochondrial Bioenergetics and Dynamism in the Failing Heart. Life (Basel) 2021; 11:436. [PMID: 34066065 PMCID: PMC8151847 DOI: 10.3390/life11050436] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/13/2022] Open
Abstract
The heart is responsible for pumping blood, nutrients, and oxygen from its cavities to the whole body through rhythmic and vigorous contractions. Heart function relies on a delicate balance between continuous energy consumption and generation that changes from birth to adulthood and depends on a very efficient oxidative metabolism and the ability to adapt to different conditions. In recent years, mitochondrial dysfunctions were recognized as the hallmark of the onset and development of manifold heart diseases (HDs), including heart failure (HF). HF is a severe condition for which there is currently no cure. In this condition, the failing heart is characterized by a disequilibrium in mitochondrial bioenergetics, which compromises the basal functions and includes the loss of oxygen and substrate availability, an altered metabolism, and inefficient energy production and utilization. This review concisely summarizes the bioenergetics and some other mitochondrial features in the heart with a focus on the features that become impaired in the failing heart.
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Affiliation(s)
- Giampaolo Morciano
- Maria Cecilia Hospital, GVM Care&Research, 48033 Cotignola, Italy
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (E.B.); (C.G.)
| | - Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (E.B.); (C.G.)
| | - Esmaa Bouhamida
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (E.B.); (C.G.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (E.B.); (C.G.)
| | - Paolo Pinton
- Maria Cecilia Hospital, GVM Care&Research, 48033 Cotignola, Italy
- Laboratory for Technologies of Advanced Therapies (LTTA), Section of Experimental Medicine, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (E.B.); (C.G.)
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18
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Modulations of Cardiac Functions and Pathogenesis by Reactive Oxygen Species and Natural Antioxidants. Antioxidants (Basel) 2021; 10:antiox10050760. [PMID: 34064823 PMCID: PMC8150787 DOI: 10.3390/antiox10050760] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/03/2021] [Accepted: 05/08/2021] [Indexed: 01/11/2023] Open
Abstract
Homeostasis in the level of reactive oxygen species (ROS) in cardiac myocytes plays a critical role in regulating their physiological functions. Disturbance of balance between generation and removal of ROS is a major cause of cardiac myocyte remodeling, dysfunction, and failure. Cardiac myocytes possess several ROS-producing pathways, such as mitochondrial electron transport chain, NADPH oxidases, and nitric oxide synthases, and have endogenous antioxidation mechanisms. Cardiac Ca2+-signaling toolkit proteins, as well as mitochondrial functions, are largely modulated by ROS under physiological and pathological conditions, thereby producing alterations in contraction, membrane conductivity, cell metabolism and cell growth and death. Mechanical stresses under hypertension, post-myocardial infarction, heart failure, and valve diseases are the main causes for stress-induced cardiac remodeling and functional failure, which are associated with ROS-induced pathogenesis. Experimental evidence demonstrates that many cardioprotective natural antioxidants, enriched in foods or herbs, exert beneficial effects on cardiac functions (Ca2+ signal, contractility and rhythm), myocytes remodeling, inflammation and death in pathological hearts. The review may provide knowledge and insight into the modulation of cardiac pathogenesis by ROS and natural antioxidants.
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Santulli G, Monaco G, Parra V, Morciano G. Editorial: Mitochondrial Remodeling and Dynamic Inter-Organellar Contacts in Cardiovascular Physiopathology. Front Cell Dev Biol 2021; 9:679725. [PMID: 33996837 PMCID: PMC8120264 DOI: 10.3389/fcell.2021.679725] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/31/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Gaetano Santulli
- Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute and Einstein Institute for Aging Research, New York, NY, United States.,Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Montefiore University Hospital, New York, NY, United States.,International Translational Research and Medical Education Academic Research Unit (ITME), Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Giovanni Monaco
- Center for Innovation and Stimulation of Drug Discovery (CISTIM), Leuven, Belgium.,Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Valentina Parra
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.,Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas y Facultad de Medicina, Universidad de Chile, Santiago, Chile.,Network for the Study of High-Lethality Cardiopulmonary Diseases (REECPAL), Universidad de Chile, Santiago, Chile
| | - Giampaolo Morciano
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.,Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy
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20
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Lim D, Semyanov A, Genazzani A, Verkhratsky A. Calcium signaling in neuroglia. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 362:1-53. [PMID: 34253292 DOI: 10.1016/bs.ircmb.2021.01.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glial cells exploit calcium (Ca2+) signals to perceive the information about the activity of the nervous tissue and the tissue environment to translate this information into an array of homeostatic, signaling and defensive reactions. Astrocytes, the best studied glial cells, use several Ca2+ signaling generation pathways that include Ca2+ entry through plasma membrane, release from endoplasmic reticulum (ER) and from mitochondria. Activation of metabotropic receptors on the plasma membrane of glial cells is coupled to an enzymatic cascade in which a second messenger, InsP3 is generated thus activating intracellular Ca2+ release channels in the ER endomembrane. Astrocytes also possess store-operated Ca2+ entry and express several ligand-gated Ca2+ channels. In vivo astrocytes generate heterogeneous Ca2+ signals, which are short and frequent in distal processes, but large and relatively rare in soma. In response to neuronal activity intracellular and inter-cellular astrocytic Ca2+ waves can be produced. Astrocytic Ca2+ signals are involved in secretion, they regulate ion transport across cell membranes, and are contributing to cell morphological plasticity. Therefore, astrocytic Ca2+ signals are linked to fundamental functions of the central nervous system ranging from synaptic transmission to behavior. In oligodendrocytes, Ca2+ signals are generated by plasmalemmal Ca2+ influx, or by release from intracellular stores, or by combination of both. Microglial cells exploit Ca2+ permeable ionotropic purinergic receptors and transient receptor potential channels as well as ER Ca2+ release. In this contribution, basic morphology of glial cells, glial Ca2+ signaling toolkit, intracellular Ca2+ signals and Ca2+-regulated functions are discussed with focus on astrocytes.
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Affiliation(s)
- Dmitry Lim
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
| | - Alexey Semyanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Moscow State University, Moscow, Russia; Sechenov First Moscow State Medical University, Moscow, Russia
| | - Armando Genazzani
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Alexei Verkhratsky
- Sechenov First Moscow State Medical University, Moscow, Russia; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; Achucarro Centre for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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21
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Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine, Danylovych Y, Danylovych H, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine, Kosterin S, Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine. ROLE OF POTASSIUM IONS IN NITRIC OXIDE BIOSYNTHESIS BY SMOOTH MUSCLE MITOCHONDRIA. FIZIOLOHICHNYĬ ZHURNAL 2021; 67:16-23. [DOI: 10.15407/fz67.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2024]
Abstract
The NO-synthase activity (mtNOS) in mitochondria of uterine smooth muscle was studied. The mitochondrial localization of NO synthesis in myocytes was proved using laser confocal microscopy method and specific fluorescent probes MitoTracker Orange (specific to mitochondria) and DAFFM (NO-sensitive fluorescent probe). It was demonstrated using flow cytometry that nitric oxide biosynthesis in isolated mytochondria decreased in the presence of a constitutive NOsynthase blocker 2-aminopyridine (100 μmol per l, 50% inhibition) and monoclonal antibodies (2.5 μg anti-Let m1 per 50 μg protein) against the H+-Ca2+-exchanger (Letm1 protein), but was’t sensitive to the mitochondrial permeability transition pore inhibitor cyclosporin A (5 μmol per l). A decrease of potassium ions concentration in the incubation medium and the presence of various types of potassium channel inhibitors significantly inhibited the NO-synthase reaction. We have concluded that potassium permeability of the inner mitochondrial membrane plays important role in the regulation of mtNOS activity.
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Singh S, Mabalirajan U. Mitochondrial calcium in command of juggling myriads of cellular functions. Mitochondrion 2021; 57:108-118. [PMID: 33412334 DOI: 10.1016/j.mito.2020.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 12/14/2020] [Accepted: 12/30/2020] [Indexed: 02/07/2023]
Abstract
The puzzling traits related to the evolutionary aspect of mitochondria, still positions the mitochondrion at the center of the research. The theory of endosymbiosis popularized by Lynn Margulis in 1967 gained prominence wherein the mitochondrion is believed to have emerged as a prokaryote and later integrated into the eukaryotic system. This semi-autonomous organelle has bagged two responsible but perilous cellular functions: a) energy metabolism, and b) calcium buffering, though both are interdependent. While most of the mitochondrial functions are saliently regulated by calcium ions, the calcium buffering role of mitochondria decides the cellular fate. Though calcium overload in few mitochondria makes them dysfunctional at the early stage of cellular stress, this doesn't lead to sudden cell death due to critical checkpoints like mitophagy, mitochondrial fusion, etc. Thus, mitochondrion juggles with multiple crucial cellular functions with its calcium buffering skill.
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Affiliation(s)
- Sabita Singh
- Molecular Pathobiology Of Respiratory Diseases, Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ulaganathan Mabalirajan
- Molecular Pathobiology Of Respiratory Diseases, Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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23
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Gutiérrez-Aguilar M. Mitochondrial calcium transport and permeability transition as rational targets for plant protection. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2020; 1861:148288. [PMID: 32800781 DOI: 10.1016/j.bbabio.2020.148288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/23/2020] [Accepted: 08/03/2020] [Indexed: 12/28/2022]
Abstract
The mitochondrial permeability transition (MPT) is a death-inducing mechanism that collapses electrochemical gradients across inner mitochondrial membranes. Several studies in model plants have detailed potential MPT-dependent cell death upon abiotic stress in response to heat shock, ultraviolet radiation, heavy metal toxicity and waterlogging. However, the molecular specifics of the MPT and its possible role on plant cell death remain controversial. This review addresses previous and recent developments on the role(s) of the MPT in plants. Considering these advances, MPT targeting can constitute a plausible strategy to ameliorate cell death in plants upon abiotic stress.
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Affiliation(s)
- Manuel Gutiérrez-Aguilar
- Departamento de Bioquímica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México City, Mexico.
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24
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Leal NS, Dentoni G, Schreiner B, Naia L, Piras A, Graff C, Cattaneo A, Meli G, Hamasaki M, Nilsson P, Ankarcrona M. Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models. Cells 2020; 9:cells9122552. [PMID: 33260715 PMCID: PMC7760163 DOI: 10.3390/cells9122552] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/19/2020] [Accepted: 11/25/2020] [Indexed: 01/24/2023] Open
Abstract
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria-ER contact sites (MERCS) are altered in Alzheimer's disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER-mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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Affiliation(s)
- Nuno Santos Leal
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
- Correspondence: (N.S.L.); (M.A.); Tel.: +44-122-333-4390 (N.S.L.); +46-852-483-577 (M.A.)
| | - Giacomo Dentoni
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Bernadette Schreiner
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Luana Naia
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Antonio Piras
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Caroline Graff
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Antonio Cattaneo
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Roma, Italy; (A.C.); (G.M.)
| | - Giovanni Meli
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Roma, Italy; (A.C.); (G.M.)
| | - Maho Hamasaki
- Department of Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;
| | - Per Nilsson
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
| | - Maria Ankarcrona
- Division of Neurogeriatrics, Department of Neurobiology, Care Science and Society, Karolinska Institutet, BioClinicum J9:20, Visionsgatan 4, 171 64 Solna, Sweden; (G.D.); (B.S.); (L.N.); (A.P.); (C.G.); (P.N.)
- Correspondence: (N.S.L.); (M.A.); Tel.: +44-122-333-4390 (N.S.L.); +46-852-483-577 (M.A.)
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English J, Son JM, Cardamone MD, Lee C, Perissi V. Decoding the rosetta stone of mitonuclear communication. Pharmacol Res 2020; 161:105161. [PMID: 32846213 PMCID: PMC7755734 DOI: 10.1016/j.phrs.2020.105161] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/04/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022]
Abstract
Cellular homeostasis in eukaryotic cells requires synchronized coordination of multiple organelles. A key role in this stage is played by mitochondria, which have recently emerged as highly interconnected and multifunctional hubs that process and coordinate diverse cellular functions. Beyond producing ATP, mitochondria generate key metabolites and are central to apoptotic and metabolic signaling pathways. Because most mitochondrial proteins are encoded in the nuclear genome, the biogenesis of new mitochondria and the maintenance of mitochondrial functions and flexibility critically depend upon effective mitonuclear communication. This review addresses the complex network of signaling molecules and pathways allowing mitochondria-nuclear communication and coordinated regulation of their independent but interconnected genomes, and discusses the extent to which dynamic communication between the two organelles has evolved for mutual benefit and for the overall maintenance of cellular and organismal fitness.
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Affiliation(s)
- Justin English
- Department of Biochemistry, Boston University, Boston, MA, 02115, USA; Graduate Program in Biomolecular Pharmacology, Department of Pharmacology and Experimental Therapeutics, Boston University, Boston, MA, 02115, USA
| | - Jyung Mean Son
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | | | - Changhan Lee
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; USC Norris Comprehensive Cancer Center, Los Angeles, CA, 90089, USA; Biomedical Sciences, Graduate School, Ajou University, Suwon, 16499, South Korea
| | - Valentina Perissi
- Department of Biochemistry, Boston University, Boston, MA, 02115, USA.
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26
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Calcium signaling and epigenetics: A key point to understand carcinogenesis. Cell Calcium 2020; 91:102285. [PMID: 32942140 DOI: 10.1016/j.ceca.2020.102285] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 02/07/2023]
Abstract
Calcium (Ca2+) signaling controls a wide range of cellular processes, including the hallmarks of cancer. The Ca2+ signaling system encompasses several types of proteins, such as receptors, channels, pumps, exchangers, buffers, and sensors, of which several are mutated or with altered expression in cancer cells. Since epigenetic mechanisms are disrupted in all stages of carcinogenesis, and reversibly regulate gene expression, they have been studied by different research groups to understand their role in Ca2+ signaling remodeling in cancer cells and the carcinogenic process. In this review, we link Ca2+ signaling, cancer, and epigenetics fields to generate a comprehensive landscape of this complex group of diseases.
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Gerdes HJ, Yang M, Heisner JS, Camara AKS, Stowe DF. Modulation of peroxynitrite produced via mitochondrial nitric oxide synthesis during Ca 2+ and succinate-induced oxidative stress in cardiac isolated mitochondria. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2020; 1861:148290. [PMID: 32828729 DOI: 10.1016/j.bbabio.2020.148290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/23/2020] [Accepted: 07/29/2020] [Indexed: 01/09/2023]
Abstract
We hypothesized that NO• is generated in isolated cardiac mitochondria as the source for ONOO- production during oxidative stress. We monitored generation of ONOO- from guinea pig isolated cardiac mitochondria subjected to excess Ca2+ uptake before adding succinate and determined if ONOO- production was dependent on a nitric oxide synthase (NOS) located in cardiac mitochondria (mtNOS). Mitochondria were suspended in experimental buffer at pH 7.15, and treated with CaCl2 and then the complex II substrate Na-succinate, followed by menadione, a quinone redox cycler, to generate O2•-. L-tyrosine was added to the mitochondrial suspension where it is oxidized by ONOO- to form dityrosine (diTyr) in proportion to the ONOO- present. We found that exposing mitochondria to excess CaCl2 before succinate resulted in an increase in diTyr and amplex red fluorescence (H2O2) signals, indicating that mitochondrial oxidant stress, induced by elevated mtCa2+ and succinate, increased mitochondrial ONOO- production via NO• and O2•-. Changes in mitochondrial ONOO- production dependent on NOS were evidenced by using NOS inhibitors L-NAME/L-NNA, TEMPOL, a superoxide dismutase (SOD) mimetic, and PTIO, a potent global NO• scavenger. L-NAME and L-NNA decreased succinate and menadione-mediated ONOO- production, PTIO decreased production of ONOO-, and TEMPOL decreased ONOO- levels by converting more O2•- to H2O2. Electron microscopy showed immuno-gold labeled iNOS and nNOS in mitochondria isolated from cardiomyocytes and heart tissue. Western blots demonstrated iNOS and nNOS bands in total heart tissue, bands for both iNOS and nNOS in β-tubulin-free non-purified (crude) mitochondrial preparations, and a prominent iNOS band, but no nNOS band, in purified (Golgi and ER-free) mitochondria. Prior treatment of guinea pigs with lipopolysacharride (LPS) enhanced expression of iNOS in liver mitochondria but not in heart mitochondria. Our results indicate that release of ONOO- into the buffer is dependent both on O2•- released from mitochondria and NO• derived from a mtCa2+-inducible nNOS isoform, possibly attached to mitochondria, and a mtNOS isoform like iNOS that is non-inducible.
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Affiliation(s)
- Harrison J Gerdes
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Meiying Yang
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - James S Heisner
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Amadou K S Camara
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - David F Stowe
- Anesthesiology Research Division, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Biomedical Engineering, Medical College of Wisconsin and Marquette University, Milwaukee, WI, USA; Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA.
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Pope NJ, Powell SM, Wigle JC, Denton ML. Wavelength- and irradiance-dependent changes in intracellular nitric oxide level. JOURNAL OF BIOMEDICAL OPTICS 2020; 25:1-20. [PMID: 32790251 PMCID: PMC7423318 DOI: 10.1117/1.jbo.25.8.085001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/23/2020] [Indexed: 06/11/2023]
Abstract
SIGNIFICANCE Photobiomodulation (PBM) refers to the beneficial effects of low-energy light absorption. Although there is a large body of literature describing downstream physiological benefits of PBM, there is a limited understanding of the molecular mechanisms underlying these effects. At present, the most popular hypothesis is that light absorption induces release of nitric oxide (NO) from the active site of cytochrome c oxidase (COX), allowing it to bind O2 instead. This is believed to increase mitochondrial respiration, and result in greater overall health of the cell due to increased adenosine triphosphate production. AIM Although NO itself is a powerful signaling molecule involved in a host of biological responses, less attention has been devoted to NO mechanisms in the context of PBM. The purpose of our work is to investigate wavelength-specific effects on intracellular NO release in living cells. APPROACH We have conducted in-depth dosimetry analyses of NO production and function in an in vitro retinal model in response to low-energy exposure to one or more wavelengths of laser light. RESULTS We found statistically significant wavelength-dependent elevations (10% to 30%) in intracellular NO levels following laser exposures at 447, 532, 635, or 808 nm. Sequential or simultaneous exposures to light at two different wavelengths enhanced the NO modulation up to 50% of unexposed controls. Additionally, the immediate increases in cellular NO levels were independent of the function of NO synthase, depended greatly on the substrate source of electrons entering the electron transport chain, and did not result in increased levels of cyclic guanosine monophosphate. CONCLUSIONS Our study concludes the simple model of light-mediated release of NO from COX is unlikely to explain the wide variety of PBM effects reported in the literature. Our multiwavelength method provides a novel tool for studying immediate and early mechanisms of PBM as well as exploring intracellular NO signaling networks.
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Affiliation(s)
- Nathaniel J. Pope
- Oak Ridge Institute of Science and Education, Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, Texas, United States
| | - Samantha M. Powell
- National Research Council, Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, Texas, United States
| | - Jeffrey C. Wigle
- Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, Texas, United States
| | - Michael L. Denton
- Air Force Research Laboratory, Joint Base San Antonio Fort Sam Houston, Texas, United States
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29
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Silzer TK, Pathak GA, Phillips NR. Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy. BMC Med Genomics 2020; 13:71. [PMID: 32429992 PMCID: PMC7236490 DOI: 10.1186/s12920-020-0727-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/29/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. METHODS Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. RESULTS Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. CONCLUSION With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.
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Affiliation(s)
- Talisa K Silzer
- Department of Microbiology, Immunology and Genetics; Graduate School of Biomedical Science, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, USA
| | - Gita A Pathak
- Department of Microbiology, Immunology and Genetics; Graduate School of Biomedical Science, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, USA
| | - Nicole R Phillips
- Department of Microbiology, Immunology and Genetics; Graduate School of Biomedical Science, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, USA.
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30
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Sterea AM, El Hiani Y. The Role of Mitochondrial Calcium Signaling in the Pathophysiology of Cancer Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1131:747-770. [PMID: 31646533 DOI: 10.1007/978-3-030-12457-1_30] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The pioneering work of Richard Altman on the presence of mitochondria in cells set in motion a field of research dedicated to uncovering the secrets of the mitochondria. Despite limitations in studying the structure and function of the mitochondria, advances in our understanding of this organelle prompted the development of potential treatments for various diseases, from neurodegenerative conditions to muscular dystrophy and cancer. As the powerhouses of the cell, the mitochondria represent the essence of cellular life and as such, a selective advantage for cancer cells. Much of the function of the mitochondria relies on Ca2+ homeostasis and the presence of effective Ca2+ signaling to maintain the balance between mitochondrial function and dysfunction and subsequently, cell survival. Ca2+ regulates the mitochondrial respiration rate which in turn increases ATP synthesis, but too much Ca2+ can also trigger the mitochondrial apoptosis pathway; however, cancer cells have evolved mechanisms to modulate mitochondrial Ca2+ influx and efflux in order to sustain their metabolic demand and ensure their survival. Therefore, targeting the mitochondrial Ca2+ signaling involved in the bioenergetic and apoptotic pathways could serve as potential approaches to treat cancer patients. This chapter will review the role of Ca2+ signaling in mediating the function of the mitochondria and its involvement in health and disease with special focus on the pathophysiology of cancer.
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Affiliation(s)
- Andra M Sterea
- Departments of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada
| | - Yassine El Hiani
- Departments of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
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Dynnik VV, Grishina EV, Fedotcheva NI. The mitochondrial NO-synthase/guanylate cyclase/protein kinase G signaling system underpins the dual effects of nitric oxide on mitochondrial respiration and opening of the permeability transition pore. FEBS J 2019; 287:1525-1536. [PMID: 31602795 DOI: 10.1111/febs.15090] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/07/2019] [Accepted: 10/09/2019] [Indexed: 12/30/2022]
Abstract
The available data on the involvement of nitric oxide (NO) and mitochondrial calcium-dependent NO synthase (mtNOS) in the control of mitochondrial respiration and the permeability transition pore (mPTP) are contradictory. We have proposed that the mitochondrial mtNOS/guanylate cyclase/protein kinase G signaling system (mtNOS-SS) is also implicated in the control of respiration and mPTP, providing the interplay between NO and mtNOS-SS, which, in turn, may result in inconsistent effects of NO. Therefore, using rat liver mitochondria, we applied specific inhibitors of the enzymes of this signaling system to evaluate its role in the control of respiration and mPTP opening. Steady-state respiration was supported by pyruvate, glutamate, or succinate in the presence of hexokinase, glucose, and ADP. When applied at low concentrations, l-arginine (to 500 µm) and NO donors (to 50 µm) activated the respiration and increased the threshold concentrations of calcium and d,l-palmitoylcarnitine required for the dissipation of the mitochondrial membrane potential and pore opening. Both effects were eliminated by the inhibitors of NO synthase, guanylate cyclase, and kinase G, which denotes the involvement of mtNOS-SS in the activation of respiration and deceleration of mPTP opening. At high concentrations, l-arginine and NO donors inhibited the respiration and promoted pore opening, indicating that adverse effects induced by an NO excess dominate over the protection provided by mtNOS-SS. Thus, these results demonstrate the opposite impact of NO and mtNOS-SS on the respiration and mPTP control, which can explain the dual effects of NO.
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Affiliation(s)
- Vladimir V Dynnik
- Department of Bioenergetics, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Puschino, Russia
| | - Elena V Grishina
- Department of Bioenergetics, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Puschino, Russia
| | - Nadezhda I Fedotcheva
- Department of Bioenergetics, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Puschino, Russia
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Bazile J, Picard B, Chambon C, Valais A, Bonnet M. Pathways and biomarkers of marbling and carcass fat deposition in bovine revealed by a combination of gel-based and gel-free proteomic analyses. Meat Sci 2019; 156:146-155. [DOI: 10.1016/j.meatsci.2019.05.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/05/2019] [Accepted: 05/16/2019] [Indexed: 01/09/2023]
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Vishnyakova PA, Tarasova NV, Volodina MA, Tsvirkun DV, Sukhanova IA, Kurchakova TA, Kan NE, Medzidova MK, Sukhikh GT, Vysokikh MY. Gestation age-associated dynamics of mitochondrial calcium uniporter subunits expression in feto-maternal complex at term and preterm delivery. Sci Rep 2019; 9:5501. [PMID: 30940880 PMCID: PMC6445111 DOI: 10.1038/s41598-019-41996-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 03/21/2019] [Indexed: 02/01/2023] Open
Abstract
Calcium plays a role of universal cellular regulator in the living cell and one of the crucial regulators of proper fetal development during gestation. Mitochondria are important for intracellular calcium handling and signaling. Mitochondrial calcium uniporter (mtCU) is a multiprotein complex of the mitochondrial inner membrane responsible for the transport of calcium to the mitochondrial matrix. In the present study, we analyzed the expression level of mtCU components in two parts of the feto-maternal system – placenta and myometrium at full-term delivery and at preterm birth (PTB) on different stages: 22–27, 28–32, 33–36 weeks of gestation (n = 50). A gradual increase of mRNA expression and changes in protein content of MCU and MICU1 subunits were revealed in the placenta during gestation. We also observed slower depolarization rate of isolated placental mitochondria induced by Ca2+ titration at PTB. In myometrium at PTB relative gene expression level of MCU, MCUb and SMDT1 increased as compared to full-term pregnancy, but the tendency to gradual increase of MCU protein simultaneous with MCUb increase and MICU1 decline was shown in gestational dynamics. Changes observed in the present study might be considered both natural dynamics as well as possible pathological mechanisms underlying preterm birth.
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Affiliation(s)
- Polina A Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia.
| | - Nadezhda V Tarasova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia.,Molecular Medicine Institute, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation, 8, Trubetskaya st., Moscow, 119991, Russia
| | - Maria A Volodina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia.,National Research University Higher School of Economics, 20, Myasnitskaya st, Moscow, 101000, Russia
| | - Daria V Tsvirkun
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia
| | - Iuliia A Sukhanova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia.,Lomonosov Moscow State University, Biology Faculty, 1/12, Leninskye gory, Moscow, 119234, Russia
| | - Tatiana A Kurchakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia
| | - Nataliya E Kan
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia
| | - Marzanat K Medzidova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia
| | - Gennadiy T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia
| | - Mikhail Yu Vysokikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4, Oparina st., Moscow, 117997, Russia.,Belozerskii Institute of Physico-chemical Biology, Lomonosov Moscow State University, 1/40, Leninskye gory, Moscow, 119234, Russia
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Kim JC, Son MJ, Woo SH. Regulation of cardiac calcium by mechanotransduction: Role of mitochondria. Arch Biochem Biophys 2018; 659:33-41. [DOI: 10.1016/j.abb.2018.09.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 09/28/2018] [Indexed: 12/27/2022]
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Morris G, Puri BK, Walder K, Berk M, Stubbs B, Maes M, Carvalho AF. The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications. Mol Neurobiol 2018; 55:8765-8787. [PMID: 29594942 PMCID: PMC6208857 DOI: 10.1007/s12035-018-1028-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/20/2018] [Indexed: 02/07/2023]
Abstract
The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted.
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Affiliation(s)
- Gerwyn Morris
- Tir Na Nog, Bryn Road seaside 87, Llanelli, Wales, SA15 2LW, UK
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia
| | - Basant K Puri
- Department of Medicine, Imperial College London, Hammersmith Hospital, London, England, W12 0HS, UK.
| | - Ken Walder
- The Centre for Molecular and Medical Research, School of Medicine, Deakin University, P.O. Box 291, Geelong, 3220, Australia
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia
- Department of Psychiatry, University of Melbourne, Melbourne, Australia
- Orygen, the National Centre of Excellence in Youth Mental Health, Parkville, Australia
- Centre for Youth Mental Health, University of Melbourne, Melbourne, Australia
- Florey Institute for Neuroscience and Mental Health, Melbourne, Australia
| | - Brendon Stubbs
- Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, UK
- Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK
| | - Michael Maes
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Australia
- Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
| | - André F Carvalho
- Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada
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B Valdez L, S Bombicino S, E Iglesias D, Rukavina Mikusic A I, Boveris A. Mitochondrial peroxynitrite generation is mainly driven by superoxide steady-state concentration rather than by nitric oxide steady-state concentration. ACTA ACUST UNITED AC 2018. [DOI: 10.15406/ijmboa.2018.03.00051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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García-Berrocoso T, Llombart V, Colàs-Campàs L, Hainard A, Licker V, Penalba A, Ramiro L, Simats A, Bustamante A, Martínez-Saez E, Canals F, Sanchez JC, Montaner J. Single Cell Immuno-Laser Microdissection Coupled to Label-Free Proteomics to Reveal the Proteotypes of Human Brain Cells After Ischemia. Mol Cell Proteomics 2017; 17:175-189. [PMID: 29133510 DOI: 10.1074/mcp.ra117.000419] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Indexed: 12/13/2022] Open
Abstract
Cerebral ischemia entails rapid tissue damage in the affected brain area causing devastating neurological dysfunction. How each component of the neurovascular unit contributes or responds to the ischemic insult in the context of the human brain has not been solved yet. Thus, the analysis of the proteome is a straightforward approach to unraveling these cell proteotypes. In this study, post-mortem brain slices from ischemic stroke patients were obtained corresponding to infarcted (IC) and contralateral (CL) areas. By means of laser microdissection, neurons and blood brain barrier structures (BBB) were isolated and analyzed using label-free quantification. MS data are available via ProteomeXchange with identifier PXD003519. Ninety proteins were identified only in neurons, 260 proteins only in the BBB and 261 proteins in both cell types. Bioinformatics analyses revealed that repair processes, mainly related to synaptic plasticity, are outlined in microdissected neurons, with nonexclusive important functions found in the BBB. A total of 30 proteins showing p < 0.05 and fold-change> 2 between IC and CL areas were considered meaningful in this study: 13 in neurons, 14 in the BBB and 3 in both cell types. Twelve of these proteins were selected as candidates and analyzed by immunohistofluorescence in independent brains. The MS findings were completely verified for neuronal SAHH2 and SRSF1 whereas the presence in both cell types of GABT and EAA2 was only validated in neurons. In addition, SAHH2 showed its potential as a prognostic biomarker of neurological improvement when analyzed early in the plasma of ischemic stroke patients. Therefore, the quantitative proteomes of neurons and the BBB (or proteotypes) after human brain ischemia presented here contribute to increasing the knowledge regarding the molecular mechanisms of ischemic stroke pathology and highlight new proteins that might represent putative biomarkers of brain ischemia or therapeutic targets.
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Affiliation(s)
- Teresa García-Berrocoso
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Víctor Llombart
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Laura Colàs-Campàs
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alexandre Hainard
- §Proteomics Core Facility, Faculty of medicine, University Medical Center, University of Geneva, Geneva, Switzerland
| | - Virginie Licker
- ¶Neuroproteomics Group, Human protein sciences department, University Medical Center, University of Geneva, Geneva, Switzerland
| | - Anna Penalba
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Laura Ramiro
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alba Simats
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Alejandro Bustamante
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Elena Martínez-Saez
- ‖Neuropathology, Pathology department, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francesc Canals
- **Proteomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jean-Charles Sanchez
- ‡‡Translational biomarker group, Human protein sciences department, University Medical Center, University of Geneva, Geneva, Switzerland
| | - Joan Montaner
- From the ‡Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain;
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Lieberman OJ, Choi SJ, Kanter E, Saverchenko A, Frier MD, Fiore GM, Wu M, Kondapalli J, Zampese E, Surmeier DJ, Sulzer D, Mosharov EV. α-Synuclein-Dependent Calcium Entry Underlies Differential Sensitivity of Cultured SN and VTA Dopaminergic Neurons to a Parkinsonian Neurotoxin. eNeuro 2017; 4:ENEURO.0167-17.2017. [PMID: 29177188 PMCID: PMC5701296 DOI: 10.1523/eneuro.0167-17.2017] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 11/01/2017] [Accepted: 11/09/2017] [Indexed: 12/27/2022] Open
Abstract
Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). We demonstrate that the higher level of neurotoxicity in SN than VTA neurons was due to SN neuron-specific toxin-induced increase in cytosolic dopamine (DA) and Ca2+, followed by an elevation of mitochondrial Ca2+, activation of nitric oxide synthase (NOS), and mitochondrial oxidation. The increase in cytosolic Ca2+ was not caused by MPP+-induced oxidative stress, but rather depended on the activity of both L-type calcium channels and aSyn expression, suggesting that these two established pathogenic factors in PD act in concert.
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Affiliation(s)
- Ori J. Lieberman
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Se Joon Choi
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Ellen Kanter
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Anastasia Saverchenko
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Micah D. Frier
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Giulia M. Fiore
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Min Wu
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
| | - Jyothisri Kondapalli
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Enrico Zampese
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - D. James Surmeier
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - David Sulzer
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
- Department of Pharmacology, Columbia University Medical Center, New York, NY 10032
| | - Eugene V. Mosharov
- New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032
- Department of Psychiatry, Columbia University Medical Center, New York, NY 10032
- Department of Neurology, Columbia University Medical Center, New York, NY 10032
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Altered Mitochondrial Metabolism and Mechanosensation in the Failing Heart: Focus on Intracellular Calcium Signaling. Int J Mol Sci 2017; 18:ijms18071487. [PMID: 28698526 PMCID: PMC5535977 DOI: 10.3390/ijms18071487] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 06/28/2017] [Accepted: 07/04/2017] [Indexed: 12/26/2022] Open
Abstract
The heart consists of millions of cells, namely cardiomyocytes, which are highly organized in terms of structure and function, at both macroscale and microscale levels. Such meticulous organization is imperative for assuring the physiological pump-function of the heart. One of the key players for the electrical and mechanical synchronization and contraction is the calcium ion via the well-known calcium-induced calcium release process. In cardiovascular diseases, the structural organization is lost, resulting in morphological, electrical, and metabolic remodeling owing the imbalance of the calcium handling and promoting heart failure and arrhythmias. Recently, attention has been focused on the role of mitochondria, which seem to jeopardize these events by misbalancing the calcium processes. In this review, we highlight our recent findings, especially the role of mitochondria (dys)function in failing cardiomyocytes with respect to the calcium machinery.
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Sepuri NBV, Angireddy R, Srinivasan S, Guha M, Spear J, Lu B, Anandatheerthavarada HK, Suzuki CK, Avadhani NG. Mitochondrial LON protease-dependent degradation of cytochrome c oxidase subunits under hypoxia and myocardial ischemia. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2017; 1858:519-528. [PMID: 28442264 PMCID: PMC5507603 DOI: 10.1016/j.bbabio.2017.04.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 04/17/2017] [Accepted: 04/21/2017] [Indexed: 01/08/2023]
Abstract
The mitochondrial ATP dependent matrix protease, Lon, is involved in the maintenance of mitochondrial DNA nucleoids and degradation of abnormal or misfolded proteins. The Lon protease regulates mitochondrial Tfam (mitochondrial transcription factor A) level and thus modulates mitochondrial DNA (mtDNA) content. We have previously shown that hypoxic stress induces the PKA-dependent phosphorylation of cytochrome c oxidase (CcO) subunits I, IVi1, and Vb and a time-dependent reduction of these subunits in RAW 264.7 murine macrophages subjected to hypoxia and rabbit hearts subjected to ischemia/reperfusion. Here, we show that Lon is involved in the preferential turnover of phosphorylated CcO subunits under hypoxic/ischemic stress. Induction of Lon protease occurs at 6 to 12 h of hypoxia and this increase coincides with lower CcO subunit contents. Over-expression of flag-tagged wild type and phosphorylation site mutant Vb and IVi1 subunits (S40A and T52A, respectively) caused marked degradation of wild type protein under hypoxia while the mutant proteins were relatively resistant. Furthermore, the recombinant purified Lon protease degraded the phosphorylated IVi1 and Vb subunits, while the phosphorylation-site mutant proteins were resistant to degradation. 3D structural modeling shows that the phosphorylation sites are exposed to the matrix compartment, accessible to matrix PKA and Lon protease. Hypoxic stress did not alter CcO subunit levels in Lon depleted cells, confirming its role in CcO turnover. Our results therefore suggest that Lon preferentially degrades the phosphorylated subunits of CcO and plays a role in the regulation of CcO activity in hypoxia and ischemia/reperfusion injury.
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Affiliation(s)
- Naresh B V Sepuri
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Rajesh Angireddy
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Satish Srinivasan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Manti Guha
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Joseph Spear
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Bin Lu
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers The State University, New Jersey Medical School, 225 Warren Street, Newark, NJ 17103-3535, USA
| | - Hindupur K Anandatheerthavarada
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA
| | - Carolyn K Suzuki
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers The State University, New Jersey Medical School, 225 Warren Street, Newark, NJ 17103-3535, USA
| | - Narayan G Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6009, USA.
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Charoensin S, Eroglu E, Opelt M, Bischof H, Madreiter-Sokolowski CT, Kirsch A, Depaoli MR, Frank S, Schrammel A, Mayer B, Waldeck-Weiermair M, Graier WF, Malli R. Intact mitochondrial Ca 2+ uniport is essential for agonist-induced activation of endothelial nitric oxide synthase (eNOS). Free Radic Biol Med 2017; 102:248-259. [PMID: 27923677 PMCID: PMC5381715 DOI: 10.1016/j.freeradbiomed.2016.11.049] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 11/14/2016] [Accepted: 11/28/2016] [Indexed: 12/18/2022]
Abstract
Mitochondrial Ca2+ uptake regulates diverse endothelial cell functions and has also been related to nitric oxide (NO•) production. However, it is not entirely clear if the organelles support or counteract NO• biosynthesis by taking up Ca2+. The objective of this study was to verify whether or not mitochondrial Ca2+ uptake influences Ca2+-triggered NO• generation by endothelial NO• synthase (eNOS) in an immortalized endothelial cell line (EA.hy926), respective primary human umbilical vein endothelial cells (HUVECs) and eNOS-RFP (red fluorescent protein) expressing human embryonic kidney (HEK293) cells. We used novel genetically encoded fluorescent NO• probes, the geNOps, and Ca2+ sensors to monitor single cell NO• and Ca2+ dynamics upon cell treatment with ATP, an inositol 1,4,5-trisphosphate (IP3)-generating agonist. Mitochondrial Ca2+ uptake was specifically manipulated by siRNA-mediated knock-down of recently identified key components of the mitochondrial Ca2+ uniporter machinery. In endothelial cells and the eNOS-RFP expressing HEK293 cells we show that reduced mitochondrial Ca2+ uptake upon the knock-down of the mitochondrial calcium uniporter (MCU) protein and the essential MCU regulator (EMRE) yield considerable attenuation of the Ca2+-triggered NO• increase independently of global cytosolic Ca2+ signals. The knock-down of mitochondrial calcium uptake 1 (MICU1), a gatekeeper of the MCU, increased both mitochondrial Ca2+ sequestration and Ca2+-induced NO• signals. The positive correlation between mitochondrial Ca2+ elevation and NO• production was independent of eNOS phosphorylation at serine1177. Our findings emphasize that manipulating mitochondrial Ca2+ uptake may represent a novel strategy to control eNOS-mediated NO• production.
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Affiliation(s)
- Suphachai Charoensin
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Emrah Eroglu
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Marissa Opelt
- Institute of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, University of Graz, Austria
| | - Helmut Bischof
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | | | - Andrijana Kirsch
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Maria R Depaoli
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Saša Frank
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Astrid Schrammel
- Institute of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, University of Graz, Austria
| | - Bernd Mayer
- Institute of Pharmaceutical Sciences, Department of Pharmacology and Toxicology, University of Graz, Austria
| | - Markus Waldeck-Weiermair
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Wolfgang F Graier
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria
| | - Roland Malli
- Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Austria.
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42
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Thuwanut P, Tipkantha W, Siriaroonrat B, Comizzoli P, Chatdarong K. Beneficial effect of extracellular adenosine 5'-triphosphate treatment on the Indochinese leopard (Panthera pardus delacouri) sperm quality after cryopreservation. Reprod Domest Anim 2016; 52 Suppl 2:269-274. [PMID: 27878881 DOI: 10.1111/rda.12854] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The Indochinese leopard (Panthera pardus delacouri) population, included in CITES Appendix I, has been declining for decades. Proper gamete preservation condition is critical for breeding programme management using artificial insemination or in vitro fertilization (IVF). The present study aimed at investigating the impact of post-thawing treatment of leopard semen with extracellular adenosine 5'-triphosphate (ATPe) on sperm quality (including morphological traits and ability to fertilize an oocyte). Semen from six adult male leopards was collected by electroejaculation (one ejaculation per cat). After the evaluation of the fresh sample quality, the semen was cryopreserved (10 × 106 cells per straw; two straws per cat). After thawing, the sperm sample from the first straw of each cat was divided into three aliquots: control (no ATPe), supplemented with 1.0 or 2.5 mM ATPe that were evaluated for sperm quality at 10, 30 min and 3 hr post-thawing. The sperm sample from the second straw, supplemented with 0, 1.0 or 2.5 mM ATPe for 30 min, was assessed for IVF with domestic cat oocytes. Sperm quality (all metrics) was negatively affected by the cryopreservation process (p ≤ .05). However, the percentage of sperm motility, level of progressive motility and percentage of plasma membrane integrity did not differ (p > .05) among post-thawing groups. The sperm mitochondrial membrane potential was enhanced (p ≤ .05) by ATPe treatment (1.0 and 2.5 mM; 10 min to 3 hr of incubation). Furthermore, incubation of ATPe (1.0 and 2.5 mM) for 30 min could promote sperm velocity patterns (curvilinear velocity; VCL and straight line velocity; VSL) (p ≤ .05). The percentage of pronuclear formation and cleaved embryos was increased (p ≤ .05) after 1.0 ATPe treatment (49.8 ± 2.8; 45.9 ± 1.5) compared to 0 mM (41.4 ± 3.3; 38.9 ± 0.5) whereas the number of sperm binding/oocyte did not significantly differ among groups. In summary, we suggest that ATPe activated the velocity of Indochinese leopard sperm motility that may lead to faster sperm/oocyte binding and sperm penetration (factors of successful embryo development).
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Affiliation(s)
- P Thuwanut
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - W Tipkantha
- Bureau of Conservation Research and Education, Zoological Park Organization (ZPO), Bangkok, Thailand
| | - B Siriaroonrat
- Bureau of Conservation Research and Education, Zoological Park Organization (ZPO), Bangkok, Thailand
| | - P Comizzoli
- Smithsonian Conservation Biology Institute, National Zoological Park, Washington, DC, USA
| | - K Chatdarong
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
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43
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Gebremeskel S, Johnston B. Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies. Oncotarget 2016; 6:41600-19. [PMID: 26486085 PMCID: PMC4747176 DOI: 10.18632/oncotarget.6113] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/22/2015] [Indexed: 01/12/2023] Open
Abstract
Chemotherapy has historically been thought to induce cancer cell death in an immunogenically silent manner. However, recent studies have demonstrated that therapeutic outcomes with specific chemotherapeutic agents (e.g. anthracyclines) correlate strongly with their ability to induce a process of immunogenic cell death (ICD) in cancer cells. This process generates a series of signals that stimulate the immune system to recognize and clear tumor cells. Extensive studies have revealed that chemotherapy-induced ICD occurs via the exposure/release of calreticulin (CALR), ATP, chemokine (C–X–C motif) ligand 10 (CXCL10) and high mobility group box 1 (HMGB1). This review provides an in-depth look into the concepts and mechanisms underlying CALR exposure, activation of the Toll-like receptor 3/IFN/CXCL10 axis, and the release of ATP and HMGB1 from dying cancer cells. Factors that influence the impact of ICD in clinical studies and the design of therapies combining chemotherapy with immunotherapy are also discussed.
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Affiliation(s)
- Simon Gebremeskel
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
| | - Brent Johnston
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.,Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada
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44
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Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlström H, Pizzo P, Ankarcrona M. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production. J Cell Mol Med 2016; 20:1686-95. [PMID: 27203684 PMCID: PMC4988279 DOI: 10.1111/jcmm.12863] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/04/2016] [Indexed: 12/28/2022] Open
Abstract
Mitochondria are physically and biochemically in contact with other organelles including the endoplasmic reticulum (ER). Such contacts are formed between mitochondria‐associated ER membranes (MAM), specialized subregions of ER, and the outer mitochondrial membrane (OMM). We have previously shown increased expression of MAM‐associated proteins and enhanced ER to mitochondria Ca2+ transfer from ER to mitochondria in Alzheimer's disease (AD) and amyloid β‐peptide (Aβ)‐related neuronal models. Here, we report that siRNA knockdown of mitofusin‐2 (Mfn2), a protein that is involved in the tethering of ER and mitochondria, leads to increased contact between the two organelles. Cells depleted in Mfn2 showed increased Ca2+ transfer from ER to mitchondria and longer stretches of ER forming contacts with OMM. Interestingly, increased contact resulted in decreased concentrations of intra‐ and extracellular Aβ40 and Aβ42. Analysis of γ‐secretase protein expression, maturation and activity revealed that the low Aβ concentrations were a result of impaired γ‐secretase complex function. Amyloid‐β precursor protein (APP), β‐site APP‐cleaving enzyme 1 and neprilysin expression as well as neprilysin activity were not affected by Mfn2 siRNA treatment. In summary, our data shows that modulation of ER–mitochondria contact affects γ‐secretase activity and Aβ generation. Increased ER–mitochondria contact results in lower γ‐secretase activity suggesting a new mechanism by which Aβ generation can be controlled.
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Affiliation(s)
- Nuno Santos Leal
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Bernadette Schreiner
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Catarina Moreira Pinho
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Riccardo Filadi
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Birgitta Wiehager
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Helena Karlström
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Paola Pizzo
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Maria Ankarcrona
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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45
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Duda J, Pötschke C, Liss B. Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease. J Neurochem 2016; 139 Suppl 1:156-178. [PMID: 26865375 PMCID: PMC5095868 DOI: 10.1111/jnc.13572] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 12/18/2022]
Abstract
Dopamine‐releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age‐dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement‐related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium‐ and activity‐dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2‐autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double‐edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed‐forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD‐paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD‐triggers, as well as on bidirectional functions of voltage‐gated L‐type calcium channels and metabolically gated ATP‐sensitive potassium (K‐ATP) channels, and their probable interplay in health and PD. ![]()
We propose that SN DA neurons possess several feedback and feed‐forward mechanisms to protect and adapt their activity‐pattern and calcium‐homeostasis within a physiological bandwidth, and that PD‐trigger factors can narrow this bandwidth. We summarize roles of ion channels in this view, and findings documenting that both, reduced as well as elevated activity and associated calcium‐levels can trigger SN DA degeneration.
This article is part of a special issue on Parkinson disease.
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Affiliation(s)
- Johanna Duda
- Department of Applied Physiology, Ulm University, Ulm, Germany
| | | | - Birgit Liss
- Department of Applied Physiology, Ulm University, Ulm, Germany.
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Randhawa PK, Jaggi AS. TRPV4 channels: physiological and pathological role in cardiovascular system. Basic Res Cardiol 2015; 110:54. [PMID: 26415881 DOI: 10.1007/s00395-015-0512-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 09/11/2015] [Accepted: 09/22/2015] [Indexed: 12/12/2022]
Abstract
TRPV4 channels are non-selective cation channels permeable to Ca(2+), Na(+), and Mg(2+) ions. Recently, TRPV4 channels have received considerable attention as these channels are widely expressed in the cardiovascular system including endothelial cells, cardiac fibroblasts, vascular smooth muscles, and peri-vascular nerves. Therefore, these channels possibly play a pivotal role in the maintenance of cardiovascular homeostasis. TRPV4 channels critically regulate flow-induced arteriogenesis, TGF-β1-induced differentiation of cardiac fibroblasts into myofibroblasts, and heart failure-induced pulmonary edema. These channels also mediate hypoxia-induced increase in proliferation and migration of pulmonary artery smooth muscle cells and progression of pulmonary hypertension. These channels also maintain flow-induced vasodilation and preserve vascular function by directly activating Ca(2+)-dependent KCa channels. Furthermore, these may also induce vasodilation and maintain blood pressure indirectly by evoking the release of NO, CGRP, and substance P. The present review discusses the evidences and the potential mechanisms implicated in diverse responses including arteriogenesis, cardiac remodeling, congestive heart failure-induced pulmonary edema, pulmonary hypertension, flow-induced dilation, regulation of blood pressure, and hypoxic preconditioning.
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Affiliation(s)
- Puneet Kaur Randhawa
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, Patiala, 147002, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, Patiala, 147002, India.
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47
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Zhang G, Wong YH, Zhang Y, He LS, Xu Y, Qian PY. Nitric oxide inhibits larval settlement in Amphibalanus amphitrite cyprids by repressing muscle locomotion and molting. Proteomics 2015; 15:3854-64. [PMID: 26316090 DOI: 10.1002/pmic.201500112] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 06/30/2015] [Accepted: 08/21/2015] [Indexed: 11/06/2022]
Abstract
Nitric oxide (NO) is a universal signaling molecule and plays a negative role in the metamorphosis of many biphasic organisms. Recently, the NO/cGMP (cyclic guanosine monophosphate) signaling pathway was reported to repress larval settlement in the barnacle Amphibalanus amphitrite. To understand the underlying molecular mechanism, we analyzed changes in the proteome of A. amphitrite cyprids in response to different concentrations of the NO donor sodium nitroprusside (SNP; 62.5, 250, and 1000 μM) using a label-free proteomics method. Compared with the control, the expression of 106 proteins differed in all three treatments. These differentially expressed proteins were assigned to 13 pathways based on KEGG pathway enrichment analysis. SNP treatment stimulated the expression of heat shock proteins and arginine kinase, which are functionally related to NO synthases, increased the expression levels of glutathione transferases for detoxification, and activated the iron-mediated fatty acid degradation pathway and the citrate cycle through ferritin. Moreover, NO repressed the level of myosins and cuticular proteins, which indicated that NO might inhibit larval settlement in A. amphitrite by modulating the process of muscle locomotion and molting.
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Affiliation(s)
- Gen Zhang
- Environmental Science Programs, School of Science, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong SAR, P. R. China.,KAUST Global Collaborative Research Program, Division of Life Science, School of Science, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong SAR, P. R. China
| | - Yue-Him Wong
- KAUST Global Collaborative Research Program, Division of Life Science, School of Science, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong SAR, P. R. China
| | - Yu Zhang
- Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Science, Shenzhen University, Shenzhen, P. R. China
| | - Li-Sheng He
- Sanya Institute of Deep-sea Science and Engineering, Chinese Academy of Science, Sanya City, Hainan Province, P. R. China
| | - Ying Xu
- Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, College of Life Science, Shenzhen University, Shenzhen, P. R. China
| | - Pei-Yuan Qian
- Environmental Science Programs, School of Science, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong SAR, P. R. China.,KAUST Global Collaborative Research Program, Division of Life Science, School of Science, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong SAR, P. R. China
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48
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Thuwanut P, Arya N, Comizzoli P, Chatdarong K. Effect of extracellular adenosine 5'-triphosphate on cryopreserved epididymal cat sperm intracellular ATP concentration, sperm quality, and in vitro fertilizing ability. Theriogenology 2015; 84:702-9. [PMID: 26050612 DOI: 10.1016/j.theriogenology.2015.05.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 04/30/2015] [Accepted: 05/03/2015] [Indexed: 02/03/2023]
Abstract
Intracellular adenosine 5'-triphosphate (ATP) is essential for supporting sperm function in the fertilization process. During cryopreservation, damage of sperm mitochondrial membrane usually leads to compromised production of intracellular ATP. Recently, extracellular ATP (ATPe) was introduced as a potent activator of sperm motility and fertilizing ability. This study aimed to evaluate (1) levels of intracellular ATP in frozen-thawed epididymal cat sperm after incubation with ATPe and (2) effects of ATPe on epididymal cat sperm parameters after freezing and thawing. Eighteen male cats were included. For each replicate, epididymal sperm from two cats were pooled to one sample (N = 9). Each pooled sample was cryopreserved with the Tris-egg yolk extender into three straws. After thawing, the first and second straws were incubated with 0-, 1.0-, or 2.5-mM ATPe for 10 minutes and evaluated for sperm quality at 10 minutes, 1, 3, and 6 hours after thawing and fertilizing ability. The third straw was evaluated for intracellular ATP concentration in control and with 2.5-mM ATPe treatment. Higher concentration of intracellular sperm ATP was observed in the samples treated with 2.5-mM ATPe compared to the controls (0.339 ± 0.06 μg/2 × 10(6) sperm vs. 0.002 ± 0.003 μg/2 × 10(6) sperm, P ≤ 0.05). In addition, incubation with 2.5-mM ATPe for 10 minutes promoted sperm motility (56.7 ± 5.0 vs. 53.3 ± 4.4%, P ≤ 0.05) and progressive motility (3.1 ± 0.2 vs. 2.8 ± 0.4, P ≤ 0.05), mitochondrial membrane potential (36.4 ± 5.5 vs. 28.7 ± 4.8%, P ≤ 0.05), and blastocyst rate (36.1 ± 7.0 and 28.8 ± 7.4%, P ≤ 0.05) compared with the controls. In contrast, ATPe remarkably interfered acrosome integrity after 6 hours of postthawed incubation. In sum, the present finding that optimal incubation time of postthaw epididymal cat sperm under proper ATPe condition might constitute a rationale for the studies on other endangered wild felids regarding sperm quality and embryo development.
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Affiliation(s)
- Paweena Thuwanut
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand; Center for Species Survival, Smithsonian Conservation Biology Institute, National Zoological Park, Washington DC, USA
| | - Nlin Arya
- Department of Preclinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Pierre Comizzoli
- Center for Species Survival, Smithsonian Conservation Biology Institute, National Zoological Park, Washington DC, USA
| | - Kaywalee Chatdarong
- Department of Obstetrics, Gynaecology and Reproduction, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
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49
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Turnbull DM, Rustin P. Genetic and biochemical intricacy shapes mitochondrial cytopathies. Neurobiol Dis 2015; 92:55-63. [PMID: 25684538 DOI: 10.1016/j.nbd.2015.02.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/22/2015] [Accepted: 02/03/2015] [Indexed: 12/17/2022] Open
Abstract
The major progress made in the identification of the molecular bases of mitochondrial disease has revealed the huge diversity of their origin. Today up to 300 mutations were identified in the mitochondrial genome and about 200 nuclear genes are possibly mutated. In this review, we highlight a number of features specific to mitochondria which possibly participate in the complexity of these diseases. These features include both the complexity of mitochondrial genetics and the multiplicity of the roles ensured by the organelles in numerous aspects of cell life and death. This spectacular complexity presumably accounts for the present lack of an efficient therapy in the vast majority of cases.
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Affiliation(s)
- Douglass M Turnbull
- Wellcome Trust Centre for Mitochondrial Research, Institute for Neuroscience, Newcastle University, Framlington Road, Newcastle upon Tyne NE2 4HH, UK
| | - Pierre Rustin
- INSERM UMR 1141, Hôpital Robert Debré, Paris, France; Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France.
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50
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Dopamine midbrain neurons in health and Parkinson’s disease: Emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels. Neuroscience 2015; 284:798-814. [DOI: 10.1016/j.neuroscience.2014.10.037] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/20/2014] [Accepted: 10/22/2014] [Indexed: 12/14/2022]
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