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Greene ES, Chen PR, Walk C, Bedford M, Dridi S. Mitochondrial dysfunction is a hallmark of woody breast myopathy in broiler chickens. Front Physiol 2025; 16:1543788. [PMID: 40034536 PMCID: PMC11872917 DOI: 10.3389/fphys.2025.1543788] [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: 12/11/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
The woody breast (WB) myopathy poses significant economic and welfare concerns to the poultry industry, however, there is no effective strategy to mitigate this pathology due to its unknown etiology. After showing previously that hypoxia is a key factor in WB progression, we used here various techniques demonstrating dysregulated mitochondria (morphology, biogenesis, tethering, function, and bioenergetics) in WB-affected muscles and in hypoxic myoblasts compared to healthy tissues and normoxic cells, respectively. The increased levels of calcium (Ca2+) in both WB-affected tissues and hypoxic myoblasts suggested that mitochondrial Ca2+ overload is likely a leading cause for mitochondrial dysfunction that merits further in-depth investigation. These findings are the first, to the best of our knowledge, to provide fundamental insights into the underlying molecular mechanisms of WB and open new vistas for understanding the interplay between calcium, mitochondrial (dys)function, and avian muscle health for subsequent development of effective preventative/corrective strategies.
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Affiliation(s)
- Elizabeth S. Greene
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United States
| | - Paula R. Chen
- USDA-ARS, Plant Genetics Research Unit, Columbia, MO, United States
| | | | | | - Sami Dridi
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United States
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2
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Makio T, Chen J, Simmen T. ER stress as a sentinel mechanism for ER Ca 2+ homeostasis. Cell Calcium 2024; 124:102961. [PMID: 39471738 DOI: 10.1016/j.ceca.2024.102961] [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: 07/31/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 11/01/2024]
Abstract
Endoplasmic reticulum (ER) stress is triggered upon the interference with oxidative protein folding that aims to produce fully folded, disulfide-bonded and glycosylated proteins, which are then competent to exit the ER. Many of the enzymes catalyzing this process require the binding of Ca2+ ions, including the chaperones BiP/GRP78, calnexin and calreticulin. The induction of ER stress with a variety of drugs interferes with chaperone Ca2+ binding, increases cytosolic Ca2+through the opening of ER Ca2+ channels, and activates store-operated Ca2+ entry (SOCE). Posttranslational modifications (PTMs) of the ER Ca2+ handling proteins through ER stress-dependent phosphorylation or oxidation control these mechanisms, as demonstrated in the case of the sarco/endoplasmic reticulum ATPase (SERCA), inositol 1,4,5 trisphosphate receptors (IP3Rs) or stromal interaction molecule 1 (STIM1). Their aim is to restore ER Ca2+ homeostasis but also to increase Ca2+ transfer from the ER to mitochondria during ER stress. This latter function boosts ER bioenergetics, but also triggers apoptosis if ER Ca2+ signaling persists. ER Ca2+ toolkit oxidative modifications upon ER stress can occur within the ER lumen or in the adjacent cytosol. Enzymes involved in this redox control include ER oxidoreductin 1 (ERO1) or the thioredoxin-family protein disulfide isomerases (PDI) and ERp57. A tight, but adaptive connection between ER Ca2+ content, ER stress and mitochondrial readouts allows for the proper functioning of many tissues, including skeletal muscle, the liver, and the pancreas, where ER stress either maintains or compromises their function, depending on its extent and context. Upon mutation of key regulators of ER Ca2+ signaling, diseases such as muscular defects (e.g., from mutated selenoprotein N, SEPN1/SELENON), or diabetes (e.g., from mutated PERK) are the result.
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Affiliation(s)
- Tadashi Makio
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Junsheng Chen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton T6G2H7, Alberta, Canada.
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3
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Vecellio Reane D, Serna JDC, Raffaello A. Unravelling the complexity of the mitochondrial Ca 2+ uniporter: regulation, tissue specificity, and physiological implications. Cell Calcium 2024; 121:102907. [PMID: 38788256 DOI: 10.1016/j.ceca.2024.102907] [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: 04/23/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024]
Abstract
Calcium (Ca2+) signalling acts a pleiotropic message within the cell that is decoded by the mitochondria through a sophisticated ion channel known as the Mitochondrial Ca2+ Uniporter (MCU) complex. Under physiological conditions, mitochondrial Ca2+ signalling is crucial for coordinating cell activation with energy production. Conversely, in pathological scenarios, it can determine the fine balance between cell survival and death. Over the last decade, significant progress has been made in understanding the molecular bases of mitochondrial Ca2+ signalling. This began with the elucidation of the MCU channel components and extended to the elucidation of the mechanisms that regulate its activity. Additionally, increasing evidence suggests molecular mechanisms allowing tissue-specific modulation of the MCU complex, tailoring channel activity to the specific needs of different tissues or cell types. This review aims to explore the latest evidence elucidating the regulation of the MCU complex, the molecular factors controlling the tissue-specific properties of the channel, and the physiological and pathological implications of mitochondrial Ca2+ signalling in different tissues.
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Affiliation(s)
- Denis Vecellio Reane
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Munich, Germany.
| | - Julian D C Serna
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Anna Raffaello
- Department of Biomedical Sciences, University of Padova, Italy.
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4
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Caggiano EG, Taniguchi CM. UCP2 and pancreatic cancer: conscious uncoupling for therapeutic effect. Cancer Metastasis Rev 2024; 43:777-794. [PMID: 38194152 PMCID: PMC11156755 DOI: 10.1007/s10555-023-10157-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 11/13/2023] [Indexed: 01/10/2024]
Abstract
Pancreatic cancer has an exaggerated dependence on mitochondrial metabolism, but methods to specifically target the mitochondria without off target effects in normal tissues that rely on these organelles is a significant challenge. The mitochondrial uncoupling protein 2 (UCP2) has potential as a cancer-specific drug target, and thus, we will review the known biology of UCP2 and discuss its potential role in the pathobiology and future therapy of pancreatic cancer.
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Affiliation(s)
- Emily G Caggiano
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Cullen M Taniguchi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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5
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Balakrishnan P, Arasu A, Velusamy T. Targeting altered calcium homeostasis and uncoupling protein-2 promotes sensitivity in drug-resistant breast cancer cells. J Biochem Mol Toxicol 2024; 38:e23575. [PMID: 37920924 DOI: 10.1002/jbt.23575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/15/2023] [Accepted: 10/18/2023] [Indexed: 11/04/2023]
Abstract
Metastatic breast cancer has the highest mortality rate among women owing to its poor clinical outcomes. Metastatic tumors pose challenges for treatment through conventional surgery or radiotherapy because of their diverse organ localization and resistance to various cytotoxic agents. Chemoresistance is a significant obstacle to effective breast cancer treatment owing to cancer's heterogeneous nature. Abnormalities in intracellular calcium signaling, coupled with altered mitochondrial metabolism, play a significant role in facilitating drug resistance and contribute to therapy resistance. Uncoupling protein-2 (UCP2) is considered as a marker of chemoresistance and is believed to play a major role in promoting metabolic shifts and tumor metastasis. In this context, it is imperative to understand the roles of altered calcium signaling and metabolic switching in the development of chemotherapeutic resistance. This study investigates the roles of UCP2 and intracellular calcium signaling (Ca2+ ) in promoting chemoresistance against cisplatin. Additionally, we explored the effectiveness of combining genipin (GP, a compound that reverses UCP2-mediated chemoresistance) and thapsigargin (TG, a calcium signaling modulator) in treating highly metastatic breast cancers. Our findings indicate that both aberrant Ca2+ signaling and metabolic shifts in cancer cells contribute to developing drug-resistant phenotypes, and the combination treatment of GP and TG significantly enhances drug sensitivity in these cells. Collectively, our study underscores the potential of these drug combinations as an effective approach to overcome drug resistance in chemoresistant cancers.
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Affiliation(s)
- Pavithra Balakrishnan
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, India
| | - Ashok Arasu
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, India
| | - Thirunavukkarasu Velusamy
- Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore, India
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6
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Kadam A, Jadiya P, Tomar D. Post-translational modifications and protein quality control of mitochondrial channels and transporters. Front Cell Dev Biol 2023; 11:1196466. [PMID: 37601094 PMCID: PMC10434574 DOI: 10.3389/fcell.2023.1196466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/24/2023] [Indexed: 08/22/2023] Open
Abstract
Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
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Affiliation(s)
- Ashlesha Kadam
- Department of Internal Medicine, Section of Cardiovascular Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Pooja Jadiya
- Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Dhanendra Tomar
- Department of Internal Medicine, Section of Cardiovascular Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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7
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Atiakshin D, Kostin A, Volodkin A, Nazarova A, Shishkina V, Esaulenko D, Buchwalow I, Tiemann M, Noda M. Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment. Pharmaceuticals (Basel) 2023; 16:817. [PMID: 37375765 DOI: 10.3390/ph16060817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/18/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly advancing, giving a reason for the optimism in several healthcare practitioners regarding the management of multiple diseases, including socially significant ones (malignant neoplasms, diabetes mellitus, viral hepatitis, mental and behavioral disorders). However, mechanisms underlying the biological effects of H2 are still being actively debated. In this review, we focus on mast cells as a potential target for H2 at the specific tissue microenvironment level. H2 regulates the processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the capacity of the integrated-buffer metabolism and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H2 and offers great opportunities for translating the obtained findings into clinical practice.
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Affiliation(s)
- Dmitri Atiakshin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, 394036 Voronezh, Russia
| | - Andrey Kostin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
| | - Artem Volodkin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
| | - Anna Nazarova
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
| | - Viktoriya Shishkina
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, 394036 Voronezh, Russia
| | - Dmitry Esaulenko
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, 394036 Voronezh, Russia
| | - Igor Buchwalow
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples' Friendship University of Russia Named after Patrice Lumumba, 117198 Moscow, Russia
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany
| | - Markus Tiemann
- Institute for Hematopathology, Fangdieckstr. 75a, 22547 Hamburg, Germany
| | - Mami Noda
- Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 816-0811, Japan
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8
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Zhou Q, Wang Y, Lu Z, He C, Li L, You M, Wang L, Cao T, Zhao Y, Li Q, Mou A, Shu W, He H, Zhao Z, Liu D, Zhu Z, Gao P, Yan Z. Cx43 acts as a mitochondrial calcium regulator that promotes obesity by inducing the polarization of macrophages in adipose tissue. Cell Signal 2023; 105:110606. [PMID: 36681290 DOI: 10.1016/j.cellsig.2023.110606] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023]
Abstract
Metabolic reprogramming of macrophages initiates the polarization of pro-inflammatory macrophages that exacerbates adipocyte dysfunction and obesity. The imbalance of mitochondrial Ca2+ homeostasis impairs mitochondrial function and promotes inflammation. Connexin 43 (Cx43), a ubiquitous gap junction protein, has been demonstrated to regulate intracellular Ca2+ homeostasis. Here we explored whether macrophage Cx43 affects the obesity process by regulating the polarization of macrophage. HFD treatment induced obesity and exacerbated macrophages infiltration with upregulation of macrophages Cx43. Macrophage-specific knockout of Cx43 reduced HFD-induced obesity by alleviating inflammation in adipose tissue, with less pro-inflammatory M1 macrophage infiltration. Consistently, inhibition or knockdown of Cx43 improved palmitic acid (PA) induced mitochondrial dysfunction, as indicated by improved oxidative phosphorylation (OXPHOS), reduced formation of mitochondria-associated membranes (MAM) and mitochondrial Ca2+ overload. Mechanistically, Cx43 interacted with the mitochondrial Ca2+ uniporter (MCU) and knockdown of Cx43 alleviated PA-induced succinate dehydrogenase (SDH) oxidation by lowering MCU-mediated mitochondrial Ca2+ uptake, which then, promoting the polarization of pro-inflammatory M1 macrophages. Thus, this study identified Cx43 as a mitochondrial Ca2+ regulator that aggravates obesity via promoting macrophages polarized to M1 pro-inflammatory phenotype and suggests that Cx43 might be a promising therapeutic target antagonizing obesity.
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Affiliation(s)
- Qing Zhou
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Yuyan Wang
- School of Medicine, Chongqing University, Chongqing, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Chengkang He
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Li Li
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Mei You
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Lijuan Wang
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Tingbing Cao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Yu Zhao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Qiang Li
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Aidi Mou
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Wentao Shu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Hongbo He
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Zhigang Zhao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Daoyan Liu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China.
| | - Peng Gao
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China.
| | - Zhencheng Yan
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China.
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9
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Oflaz FE, Koshenov Z, Hirtl M, Bachkoenig OA, Graier WF, Gottschalk B. Synergy of Uncoupling Proteins (1 and 2) with Mitochondrial Ca2+ Uptake Machinery Potentiate Mitochondrial Uncoupling. Cell Calcium 2023; 112:102736. [PMID: 37031662 DOI: 10.1016/j.ceca.2023.102736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/07/2023]
Abstract
Mitochondrial uncoupling proteins UCP1 and UCP2 have a structural homology of app. 60%. They execute their mitochondria uncoupling function through different molecular mechanisms. Non-shivering thermogenesis by UCP1 is mediated through a transmembrane dissipation of the proton motive force to create heat during sympathetic stimulation. UCP2, on the other hand, modulates through the interaction with methylated MICU1 the permeability of the cristae junction, which acts as an isolator for the cristae-located mitochondrial membrane potential. In this mini-review, we discuss and compare the recently described molecular mechanism of UCP1 in brown adipose tissue and UCP2 in aged and cancer non-excitable cells that contribute to mitochondrial uncoupling, and the synergistic effects of both UCPs with the mitochondrial Ca2+ uptake machinery.
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Affiliation(s)
- Furkan E Oflaz
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria
| | - Zhanat Koshenov
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria
| | - Martin Hirtl
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria
| | - Olaf A Bachkoenig
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria
| | - Wolfgang F Graier
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria; BioTechMed, Graz, Austria.
| | - Benjamin Gottschalk
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/4, Graz, 8010 Austria
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10
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Luby A, Alves-Guerra MC. UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control. Int J Mol Sci 2022; 23:ijms232315077. [PMID: 36499405 PMCID: PMC9735768 DOI: 10.3390/ijms232315077] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.
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11
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Bachkoenig OA, Gottschalk B, Malli R, Graier WF. An unexpected effect of risperidone reveals a nonlinear relationship between cytosolic Ca 2+ and mitochondrial Ca 2+ uptake. CURRENT TOPICS IN MEMBRANES 2022; 90:13-35. [PMID: 36368872 DOI: 10.1016/bs.ctm.2022.09.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Mitochondria actively contribute to cellular Ca2+ homeostasis. The molecular mechanisms of mitochondrial Ca2+ uptake and release are well characterized and are attributed to the multi-protein assembly of the mitochondrial Ca2+ uniporter complex (MCUC) and the mitochondrial sodium-calcium exchanger (NCLX), respectively. Hence, Ca2+ transfer from the endoplasmic reticulum (ER) and store-operated Ca2+ entry (SOCE) into the mitochondrial matrix has been quantitatively visualized on the subcellular level using targeted fluorescent biosensors. However, a correlation between the amplitude of cytosolic Ca2+ elevation with that in the mitochondrial matrix has not been investigated in detail so far. In the present study, we combined the Ca2+-mobilizing agonist histamine with the H1-receptor antagonist risperidone to establish a well-tunable experimental approach allowing the correlation between low, slow, high, and fast cytosolic and mitochondrial Ca2+ signals in response to inositol 1,4,5-trisphosphate (IP3)-triggered ER Ca2+ release. Our present data confirm a defined threshold in cytosolic Ca2+, which is necessary for the activation of mitochondrial Ca2+ uptake. Moreover, our data support the hypothesis of different modes of mitochondrial Ca2+ uptake depending on the source of the ion (i.e., ER vs SOCE).
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Affiliation(s)
- Olaf A Bachkoenig
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Benjamin Gottschalk
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Roland Malli
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Wolfgang F Graier
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
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12
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Mohammadi A, Higazy R, Gauda EB. PGC-1α activity and mitochondrial dysfunction in preterm infants. Front Physiol 2022; 13:997619. [PMID: 36225305 PMCID: PMC9548560 DOI: 10.3389/fphys.2022.997619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
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Affiliation(s)
- Atefeh Mohammadi
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Randa Higazy
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
| | - Estelle B. Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- *Correspondence: Estelle B. Gauda,
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13
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Inoue R, Tsuno T, Togashi Y, Okuyama T, Sato A, Nishiyama K, Kyohara M, Li J, Fukushima S, Kin T, Miyashita D, Shiba Y, Atobe Y, Kiyonari H, Bando K, Shapiro AJ, Funakoshi K, Kulkarni RN, Terauchi Y, Shirakawa J. Uncoupling protein 2 and aldolase B impact insulin release by modulating mitochondrial function and Ca 2+ release from the ER. iScience 2022; 25:104603. [PMID: 35800776 PMCID: PMC9253497 DOI: 10.1016/j.isci.2022.104603] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 03/25/2022] [Accepted: 06/08/2022] [Indexed: 02/02/2023] Open
Abstract
Uncoupling protein 2 (UCP2), a mitochondrial protein, is known to be upregulated in pancreatic islets of patients with type 2 diabetes (T2DM); however, the pathological significance of this increase in UCP2 expression is unclear. In this study, we highlight the molecular link between the increase in UCP2 expression in β-cells and β-cell failure by using genetically engineered mice and human islets. β-cell-specific UCP2-overexpressing transgenic mice (βUCP2Tg) exhibited glucose intolerance and a reduction in insulin secretion. Decreased mitochondrial function and increased aldolase B (AldB) expression through oxidative-stress-mediated pathway were observed in βUCP2Tg islets. AldB, a glycolytic enzyme, was associated with reduced insulin secretion via mitochondrial dysfunction and impaired calcium release from the endoplasmic reticulum (ER). Taken together, our findings provide a new mechanism of β-cell dysfunction by UCP2 and AldB. Targeting the UCP2/AldB axis is a promising approach for the recovery of β-cell function.
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Affiliation(s)
- Ryota Inoue
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Takahiro Tsuno
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Tomoko Okuyama
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Aoi Sato
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Kuniyuki Nishiyama
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Mayu Kyohara
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jinghe Li
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Setsuko Fukushima
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
| | - Tatsuya Kin
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Daisuke Miyashita
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yusuke Shiba
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Yoshitoshi Atobe
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Hiroshi Kiyonari
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - Kana Bando
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan
| | - A.M. James Shapiro
- Clinical Islet Laboratory and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G2C8, Canada
| | - Kengo Funakoshi
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
| | - Rohit N. Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
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14
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Gottschalk B, Koshenov Z, Waldeck-Weiermair M, Radulović S, Oflaz FE, Hirtl M, Bachkoenig OA, Leitinger G, Malli R, Graier WF. MICU1 controls spatial membrane potential gradients and guides Ca 2+ fluxes within mitochondrial substructures. Commun Biol 2022; 5:649. [PMID: 35778442 PMCID: PMC9249747 DOI: 10.1038/s42003-022-03606-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 06/17/2022] [Indexed: 01/19/2023] Open
Abstract
Mitochondrial ultrastructure represents a pinnacle of form and function, with the inner mitochondrial membrane (IMM) forming isolated pockets of cristae membrane (CM), separated from the inner-boundary membrane (IBM) by cristae junctions (CJ). Applying structured illumination and electron microscopy, a novel and fundamental function of MICU1 in mediating Ca2+ control over spatial membrane potential gradients (SMPGs) between CM and IMS was identified. We unveiled alterations of SMPGs by transient CJ openings when Ca2+ binds to MICU1 resulting in spatial cristae depolarization. This Ca2+/MICU1-mediated plasticity of the CJ further provides the mechanistic bedrock of the biphasic mitochondrial Ca2+ uptake kinetics via the mitochondrial Ca2+ uniporter (MCU) during intracellular Ca2+ release: Initially, high Ca2+ opens CJ via Ca2+/MICU1 and allows instant Ca2+ uptake across the CM through constantly active MCU. Second, MCU disseminates into the IBM, thus establishing Ca2+ uptake across the IBM that circumvents the CM. Under the condition of MICU1 methylation by PRMT1 in aging or cancer, UCP2 that binds to methylated MICU1 destabilizes CJ, disrupts SMPGs, and facilitates fast Ca2+ uptake via the CM.
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Affiliation(s)
- Benjamin Gottschalk
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Zhanat Koshenov
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Markus Waldeck-Weiermair
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Snježana Radulović
- Gottfried Schatz Research Center: Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria
| | - Furkan E Oflaz
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Martin Hirtl
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Olaf A Bachkoenig
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Gerd Leitinger
- Gottfried Schatz Research Center: Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria
| | - Roland Malli
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Wolfgang F Graier
- Gottfried Schatz Research Center: Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
- BioTechMed Graz, Graz, Austria.
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15
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Zhang L, Qi J, Zhang X, Zhao X, An P, Luo Y, Luo J. The Regulatory Roles of Mitochondrial Calcium and the Mitochondrial Calcium Uniporter in Tumor Cells. Int J Mol Sci 2022; 23:ijms23126667. [PMID: 35743109 PMCID: PMC9223557 DOI: 10.3390/ijms23126667] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/10/2022] [Accepted: 06/10/2022] [Indexed: 02/06/2023] Open
Abstract
Mitochondria, as the main site of cellular energy metabolism and the generation of oxygen free radicals, are the key switch for mitochondria-mediated endogenous apoptosis. Ca2+ is not only an important messenger for cell proliferation, but it is also an indispensable signal for cell death. Ca2+ participates in and plays a crucial role in the energy metabolism, physiology, and pathology of mitochondria. Mitochondria control the uptake and release of Ca2+ through channels/transporters, such as the mitochondrial calcium uniporter (MCU), and influence the concentration of Ca2+ in both mitochondria and cytoplasm, thereby regulating cellular Ca2+ homeostasis. Mitochondrial Ca2+ transport-related processes are involved in important biological processes of tumor cells including proliferation, metabolism, and apoptosis. In particular, MCU and its regulatory proteins represent a new era in the study of MCU-mediated mitochondrial Ca2+ homeostasis in tumors. Through an in-depth analysis of the close correlation between mitochondrial Ca2+ and energy metabolism, autophagy, and apoptosis of tumor cells, we can provide a valuable reference for further understanding of how mitochondrial Ca2+ regulation helps diagnosis and therapy.
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Affiliation(s)
- Linlin Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
| | - Jingyi Qi
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
| | - Xu Zhang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
| | - Xiya Zhao
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
| | - Peng An
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
- Correspondence: (P.A.); (Y.L.); (J.L.)
| | - Yongting Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
- Correspondence: (P.A.); (Y.L.); (J.L.)
| | - Junjie Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China; (J.Q.); (X.Z.); (X.Z.)
- Correspondence: (P.A.); (Y.L.); (J.L.)
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16
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Matuz-Mares D, González-Andrade M, Araiza-Villanueva MG, Vilchis-Landeros MM, Vázquez-Meza H. Mitochondrial Calcium: Effects of Its Imbalance in Disease. Antioxidants (Basel) 2022; 11:antiox11050801. [PMID: 35624667 PMCID: PMC9138001 DOI: 10.3390/antiox11050801] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 02/06/2023] Open
Abstract
Calcium is used in many cellular processes and is maintained within the cell as free calcium at low concentrations (approximately 100 nM), compared with extracellular (millimolar) concentrations, to avoid adverse effects such as phosphate precipitation. For this reason, cells have adapted buffering strategies by compartmentalizing calcium into mitochondria and the endoplasmic reticulum (ER). In mitochondria, the calcium concentration is in the millimolar range, as it is in the ER. Mitochondria actively contribute to buffering cellular calcium, but if matrix calcium increases beyond physiological demands, it can promote the opening of the mitochondrial permeability transition pore (mPTP) and, consequently, trigger apoptotic or necrotic cell death. The pathophysiological implications of mPTP opening in ischemia-reperfusion, liver, muscle, and lysosomal storage diseases, as well as those affecting the central nervous system, for example, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have been reported. In this review, we present an updated overview of the main cellular mechanisms of mitochondrial calcium regulation. We specially focus on neurodegenerative diseases related to imbalances in calcium homeostasis and summarize some proposed therapies studied to attenuate these diseases.
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Affiliation(s)
- Deyamira Matuz-Mares
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Cd. Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.M.-M.); (M.G.-A.); (M.M.V.-L.)
| | - Martin González-Andrade
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Cd. Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.M.-M.); (M.G.-A.); (M.M.V.-L.)
| | | | - María Magdalena Vilchis-Landeros
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Cd. Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.M.-M.); (M.G.-A.); (M.M.V.-L.)
| | - Héctor Vázquez-Meza
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Cd. Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (D.M.-M.); (M.G.-A.); (M.M.V.-L.)
- Correspondence: ; Tel.: +52-55-5623-2168
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17
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Hulsurkar MM, Lahiri SK, Karch J, Wang MC, Wehrens XHT. Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases. Expert Opin Ther Targets 2022; 26:303-317. [PMID: 35426759 PMCID: PMC9081256 DOI: 10.1080/14728222.2022.2067479] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/14/2022] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Abnormal calcium signaling between organelles such as the sarcoplasmic reticulum (SR), mitochondria and lysosomes is a key feature of heart diseases. Calcium serves as a secondary messenger mediating inter-organellar crosstalk, essential for maintaining the cardiomyocyte function. AREAS COVERED This article examines the available literature related to calcium channels and transporters involved in inter-organellar calcium signaling. The SR calcium-release channels ryanodine receptor type-2 (RyR2) and inositol 1,4,5-trisphosphate receptor (IP3R), and calcium-transporter SR/ER-ATPase 2a (SERCA2a) are illuminated. The roles of mitochondrial voltage-dependent anion channels (VDAC), the mitochondria Ca2+ uniporter complex (MCUC), and the lysosomal H+/Ca2+ exchanger, two pore channels (TPC), and transient receptor potential mucolipin (TRPML) are discussed. Furthermore, recent studies showing calcium-mediated crosstalk between the SR, mitochondria, and lysosomes as well as how this crosstalk is dysregulated in cardiac diseases are placed under the spotlight. EXPERT OPINION Enhanced SR calcium release via RyR2 and reduced SR reuptake via SERCA2a, increased VDAC and MCUC-mediated calcium uptake into mitochondria, and enhanced lysosomal calcium-release via lysosomal TPC and TRPML may all contribute to aberrant calcium homeostasis causing heart disease. While mechanisms of this crosstalk need to be studied further, interventions targeting these calcium channels or combinations thereof might represent a promising therapeutic strategy.
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Affiliation(s)
- Mohit M Hulsurkar
- Baylor College of Medicine, Houston TX USA
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Satadru K Lahiri
- Baylor College of Medicine, Houston TX USA
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Jason Karch
- Baylor College of Medicine, Houston TX USA
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
| | - Meng C Wang
- Baylor College of Medicine, Houston TX USA
- Huffington Center on Aging, Baylor College of Medicine, Houston TX USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Xander H T Wehrens
- Baylor College of Medicine, Houston TX USA
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA
- Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX, USA
- Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA
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18
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Garbincius JF, Elrod JW. Mitochondrial calcium exchange in physiology and disease. Physiol Rev 2022; 102:893-992. [PMID: 34698550 PMCID: PMC8816638 DOI: 10.1152/physrev.00041.2020] [Citation(s) in RCA: 193] [Impact Index Per Article: 64.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 08/16/2021] [Accepted: 10/19/2021] [Indexed: 12/13/2022] Open
Abstract
The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (mCa2+) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for mCa2+ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of mCa2+ transport and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of mCa2+ flux and evaluate how alterations in mCa2+ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant mCa2+ handling and by summarizing critical unanswered questions regarding the biology of mCa2+ flux.
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Affiliation(s)
- Joanne F Garbincius
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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19
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Mitochondrial Ca 2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling. Int J Mol Sci 2022; 23:ijms23063025. [PMID: 35328444 PMCID: PMC8954803 DOI: 10.3390/ijms23063025] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/03/2022] [Indexed: 01/27/2023] Open
Abstract
Mitochondria are the sites of oxidative metabolism in eukaryotes where the metabolites of sugars, fats, and amino acids are oxidized to harvest energy. Notably, mitochondria store Ca2+ and work in synergy with organelles such as the endoplasmic reticulum and extracellular matrix to control the dynamic balance of Ca2+ concentration in cells. Mitochondria are the vital organelles in heart tissue. Mitochondrial Ca2+ homeostasis is particularly important for maintaining the physiological and pathological mechanisms of the heart. Mitochondrial Ca2+ homeostasis plays a key role in the regulation of cardiac energy metabolism, mechanisms of death, oxygen free radical production, and autophagy. The imbalance of mitochondrial Ca2+ balance is closely associated with cardiac remodeling. The mitochondrial Ca2+ uniporter (mtCU) protein complex is responsible for the uptake and release of mitochondrial Ca2+ and regulation of Ca2+ homeostasis in mitochondria and consequently, in cells. This review summarizes the mechanisms of mitochondrial Ca2+ homeostasis in physiological and pathological cardiac remodeling and the regulatory effects of the mitochondrial calcium regulatory complex on cardiac energy metabolism, cell death, and autophagy, and also provides the theoretical basis for mitochondrial Ca2+ as a novel target for the treatment of cardiovascular diseases.
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20
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Tawfik I, Gottschalk B, Jarc A, Bresilla D, Rost R, Obermayer-Pietsch B, Graier WF, Madreiter-Sokolowski CT. T3-induced enhancement of mitochondrial Ca 2+ uptake as a boost for mitochondrial metabolism. Free Radic Biol Med 2022; 181:197-208. [PMID: 35091061 DOI: 10.1016/j.freeradbiomed.2022.01.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/24/2022] [Indexed: 12/15/2022]
Abstract
Thyroid hormones act as master regulators of cellular metabolism. Thereby, the biologically active triiodothyronine (T3) induces the expression of genes to enhance mitochondrial metabolic function. Notably, Ca2+ ions are necessary for the activity of dehydrogenases of the tricarboxylic acid cycle and, thus, mitochondrial respiration. We investigated whether treating HeLa cells with T3 causes alterations in mitochondrial Ca2+ ([Ca2+]mito) levels. Real-time measurements by fluorescence microscopy revealed that treatment with T3 for 3 h induces a significant increase in basal [Ca2+]mito levels and [Ca2+]mito uptake upon the depletion of the endoplasmic reticulum (ER) Ca2+ store, while cytosolic Ca2+ levels remained unchanged. T3 incubation was found to upregulate mRNA expression levels of uncoupling proteins 2 and 3 (UCP2, UCP3) and of protein arginine methyltransferase 1 (PRMT1). Live-cell imaging revealed that T3-induced enhancement of mitochondrial Ca2+ uptake depends on the mitochondrial Ca2+ uniporter (MCU), UCP2, and PRMT1 that are essential for increased mitochondrial ATP ([ATP]mito) production after T3 treatment. Besides, increased [Ca2+]mito and [ATP]mito levels correlated with enhanced production of reactive oxygen species (ROS) in mitochondria. Notably, ROS scavenging causes mitochondrial Ca2+ elevation and outplays the impact of T3 on [Ca2+]mito homeostasis. Based on these results, we assume that thyroid hormones adjust [Ca2+]mito homeostasis by modulating the UCP2- and PRMT1-balanced [Ca2+]mito uptake via MCU in case of physiological ROS levels to convey their impact on mitochondrial ATP and ROS production.
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Affiliation(s)
- Ines Tawfik
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Benjamin Gottschalk
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Angelo Jarc
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Doruntina Bresilla
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Rene Rost
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria
| | - Barbara Obermayer-Pietsch
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrinology Lab Platform, Medical University of Graz, Auenbruggerplatz 15, 8010, Graz, Austria
| | - Wolfgang F Graier
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria; BioTechMed, Graz, Austria
| | - Corina T Madreiter-Sokolowski
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010, Graz, Austria.
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21
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Gomes MT, Bai Y, Potje SR, Zhang L, Lockett AD, Machado RF. Signal Transduction during Metabolic and Inflammatory Reprogramming in Pulmonary Vascular Remodeling. Int J Mol Sci 2022; 23:2410. [PMID: 35269553 PMCID: PMC8910500 DOI: 10.3390/ijms23052410] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [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: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by (mal)adaptive remodeling of the pulmonary vasculature, which is associated with inflammation, fibrosis, thrombosis, and neovascularization. Vascular remodeling in PAH is associated with cellular metabolic and inflammatory reprogramming that induce profound endothelial and smooth muscle cell phenotypic changes. Multiple signaling pathways and regulatory loops act on metabolic and inflammatory mediators which influence cellular behavior and trigger pulmonary vascular remodeling in vivo. This review discusses the role of bioenergetic and inflammatory impairments in PAH development.
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Affiliation(s)
- Marta T. Gomes
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
| | - Yang Bai
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
- Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China
| | - Simone R. Potje
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
- Department of Biological Science, Minas Gerais State University (UEMG), Passos 37900-106, Brazil
| | - Lu Zhang
- Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang 110122, China;
| | - Angelia D. Lockett
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
| | - Roberto F. Machado
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; (Y.B.); (S.R.P.); (A.D.L.)
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22
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Hirschenson J, Melgar-Bermudez E, Mailloux RJ. The Uncoupling Proteins: A Systematic Review on the Mechanism Used in the Prevention of Oxidative Stress. Antioxidants (Basel) 2022; 11:antiox11020322. [PMID: 35204205 PMCID: PMC8868465 DOI: 10.3390/antiox11020322] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/12/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Mitochondrial uncoupling proteins (UCP) 1-3 fulfill many physiological functions, ranging from non-shivering thermogenesis (UCP1) to glucose-stimulated insulin release (GSIS) and satiety signaling (UCP2) and muscle fuel metabolism (UCP3). Several studies have suggested that UCPs mediate these functions by facilitating proton return to the matrix. This would decrease protonic backpressure on the respiratory chain, lowering the production of hydrogen peroxide (H2O2), a second messenger. However, controlling mitochondrial H2O2 production to prevent oxidative stress by activating these leaks through these proteins is still enthusiastically debated. This is due to compelling evidence that UCP2/3 fulfill other function(s) and the inability to reproduce findings that UCP1-3 use inducible leaks to control reactive oxygen species (ROS) production. Further, other studies have found that UCP2/3 may serve as Ca2+. Therefore, we performed a systematic review aiming to summarize the results collected on the topic. A literature search using a list of curated keywords in Pubmed, BIOSIS Citation Index and Scopus was conducted. Potentially relevant references were screened, duplicate references eliminated, and then literature titles and abstracts were evaluated using Rayyan software. A total of 1101 eligible studies were identified for the review. From this total, 416 studies were evaluated based on our inclusion criteria. In general, most studies identified a role for UCPs in preventing oxidative stress, and in some cases, this may be related to the induction of leaks and lowering protonic backpressure on the respiratory chain. However, some studies also generated evidence that UCP2/3 may mitigate oxidative stress by transporting Ca2+ into the matrix, exporting lipid hydroperoxides, or by transporting C-4 metabolites. Additionally, some showed that activating UCP1 or 3 can increase mitochondrial ROS production, even though there is still augmented protection from oxidative stress. Conclusion: Overall, most available studies demonstrate that UCPs, particularly UCP2/3, prevent oxidative stress. However, the mechanism utilized to do so remains elusive and raises the question that UCP2/3 should be renamed, since they may still not be true “uncoupling proteins”.
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23
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Uncoupling Proteins and Regulated Proton Leak in Mitochondria. Int J Mol Sci 2022; 23:ijms23031528. [PMID: 35163451 PMCID: PMC8835771 DOI: 10.3390/ijms23031528] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/26/2022] [Indexed: 12/17/2022] Open
Abstract
Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons to the matrix. This proton transport can take place through ATP synthase complex (leading to formation of ATP) or can occur via proton transporters of the mitochondrial carrier superfamily and/or membrane lipids. Some mitochondrial proton transporters, such as uncoupling proteins (UCPs), transport protons as their general regulating function; while others are symporters or antiporters, which use the proton gradient as a driving force to co-transport other substrates across the mitochondrial inner membrane (such as phosphate carrier, a symporter; or aspartate/glutamate transporter, an antiporter). Passage (or leakage) of protons across the inner membrane to matrix from any route other than ATP synthase negatively impacts ATP synthesis. The focus of this review is on regulated proton transport by UCPs. Recent findings on the structure and function of UCPs, and the related research methodologies, are also critically reviewed. Due to structural similarity of members of the mitochondrial carrier superfamily, several of the known structural features are potentially expandable to all members. Overall, this report provides a brief, yet comprehensive, overview of the current knowledge in the field.
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24
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Zhang Y, Zervopoulos SD, Boukouris AE, Lorenzana-Carrillo MA, Saleme B, Webster L, Liu Y, Haromy A, Tabatabaei Dakhili SA, Ussher JR, Sutendra G, Michelakis ED. SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes. J Am Heart Assoc 2021; 10:e020451. [PMID: 34719264 PMCID: PMC9075406 DOI: 10.1161/jaha.120.020451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Isolated loss‐of‐function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10‐year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose‐dependent manner), along with insulin resistance, compared with wild‐type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild‐type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.
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Affiliation(s)
- Yongneng Zhang
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Sotirios D Zervopoulos
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Aristeidis E Boukouris
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | | | - Bruno Saleme
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Linda Webster
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Yongsheng Liu
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Alois Haromy
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | | | - John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta Edmonton Alberta Canada
| | - Gopinath Sutendra
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
| | - Evangelos D Michelakis
- Department of Medicine (Cardiology), Faculty of Medicine and Dentistry University of Alberta Edmonton Alberta Canada
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25
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Putative role of uncoupling proteins in mitochondria-nucleus communications and DNA damage response. J Biosci 2021. [DOI: 10.1007/s12038-021-00224-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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26
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Huang HR, Cho SJ, Harris RM, Yang J, Bermejo S, Sharma L, Dela Cruz CS, Xu JF, Stout-Delgado HW. RIPK3 Activates MLKL-mediated Necroptosis and Inflammasome Signaling during Streptococcus Infection. Am J Respir Cell Mol Biol 2021; 64:579-591. [PMID: 33625952 DOI: 10.1165/rcmb.2020-0312oc] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, Streptococcus pneumoniae is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an in vivo murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during S. pneumoniae infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS-AKT pathway to protect against S. pneumoniae. In conclusion, our study demonstrated a mechanism by which RIPK3-initiated necroptosis is essential for host defense against S. pneumoniae.
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Affiliation(s)
- Hua-Rong Huang
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York.,Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; and
| | - Soo Jung Cho
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York
| | - Rebecca M Harris
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York
| | - Jianjun Yang
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York
| | - Santos Bermejo
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Lokesh Sharma
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Charles S Dela Cruz
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Jin-Fu Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; and
| | - Heather W Stout-Delgado
- Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York
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27
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Hypoxia and the integrated stress response promote pulmonary hypertension and preeclampsia: Implications in drug development. Drug Discov Today 2021; 26:2754-2773. [PMID: 34302972 DOI: 10.1016/j.drudis.2021.07.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 03/31/2021] [Accepted: 07/14/2021] [Indexed: 11/21/2022]
Abstract
Chronic hypoxia is a common cause of pulmonary hypertension, preeclampsia, and intrauterine growth restriction (IUGR). The molecular mechanisms underlying these diseases are not completely understood. Chronic hypoxia may induce the generation of reactive oxygen species (ROS) in mitochondria, promote endoplasmic reticulum (ER) stress, and result in the integrated stress response (ISR) in the pulmonary artery and uteroplacental tissues. Numerous studies have implicated hypoxia-inducible factors (HIFs), oxidative stress, and ER stress/unfolded protein response (UPR) in the development of pulmonary hypertension, preeclampsia and IUGR. This review highlights the roles of HIFs, mitochondria-derived ROS and UPR, as well as their interplay, in the pathogenesis of pulmonary hypertension and preeclampsia, and their implications in drug development.
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28
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Wu D, Dasgupta A, Read AD, Bentley RET, Motamed M, Chen KH, Al-Qazazi R, Mewburn JD, Dunham-Snary KJ, Alizadeh E, Tian L, Archer SL. Oxygen sensing, mitochondrial biology and experimental therapeutics for pulmonary hypertension and cancer. Free Radic Biol Med 2021; 170:150-178. [PMID: 33450375 PMCID: PMC8217091 DOI: 10.1016/j.freeradbiomed.2020.12.452] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023]
Abstract
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling molecule, hydrogen peroxide (H2O2), by superoxide dismutase (SOD2). H2O2 exits the mitochondria and regulates ion channels and enzymes, altering plasma membrane potential, intracellular Ca2+ and Ca2+-sensitization and controlling acute, adaptive, responses to hypoxia that involve changes in ventilation, vascular tone and neurotransmitter release. Subversion of this O2-sensing pathway creates a pseudohypoxic state that promotes disease progression in pulmonary arterial hypertension (PAH) and cancer. Pseudohypoxia is a state in which biochemical changes, normally associated with hypoxia, occur despite normal pO2. Epigenetic silencing of SOD2 by DNA methylation alters H2O2 production, activating hypoxia-inducible factor 1α, thereby disrupting mitochondrial metabolism and dynamics, accelerating cell proliferation and inhibiting apoptosis. Other epigenetic mechanisms, including dysregulation of microRNAs (miR), increase pyruvate dehydrogenase kinase and pyruvate kinase muscle isoform 2 expression in both diseases, favoring uncoupled aerobic glycolysis. This Warburg metabolic shift also accelerates cell proliferation and impairs apoptosis. Disordered mitochondrial dynamics, usually increased mitotic fission and impaired fusion, promotes disease progression in PAH and cancer. Epigenetic upregulation of dynamin-related protein 1 (Drp1) and its binding partners, MiD49 and MiD51, contributes to the pathogenesis of PAH and cancer. Finally, dysregulation of intramitochondrial Ca2+, resulting from impaired mitochondrial calcium uniporter complex (MCUC) function, links abnormal mitochondrial metabolism and dynamics. MiR-mediated decreases in MCUC function reduce intramitochondrial Ca2+, promoting Warburg metabolism, whilst increasing cytosolic Ca2+, promoting fission. Epigenetically disordered mitochondrial O2-sensing, metabolism, dynamics, and Ca2+ homeostasis offer new therapeutic targets for PAH and cancer. Promoting glucose oxidation, restoring the fission/fusion balance, and restoring mitochondrial calcium regulation are promising experimental therapeutic strategies.
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Affiliation(s)
- Danchen Wu
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Asish Dasgupta
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Austin D Read
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Rachel E T Bentley
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Mehras Motamed
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kuang-Hueih Chen
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Ruaa Al-Qazazi
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Jeffrey D Mewburn
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada
| | - Kimberly J Dunham-Snary
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Elahe Alizadeh
- Queen's Cardiopulmonary Unit (QCPU), Department of Medicine, Queen's University, 116 Barrie Street, Kingston, ON, K7L 3J9, Canada
| | - Lian Tian
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK
| | - Stephen L Archer
- Department of Medicine, Queen's University, 94 Stuart St., Kingston, Ontario, K7L 3N6, Canada.
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29
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Nakamura T, Ogawa M, Kojima K, Takayanagi S, Ishihara S, Hattori K, Naguro I, Ichijo H. The mitochondrial Ca 2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis. EMBO Rep 2021; 22:e51532. [PMID: 33822458 PMCID: PMC8097382 DOI: 10.15252/embr.202051532] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemia-reperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.
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Affiliation(s)
- Toshitaka Nakamura
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Motoyuki Ogawa
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Kazuki Kojima
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Saki Takayanagi
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Shunya Ishihara
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Kazuki Hattori
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Isao Naguro
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
| | - Hidenori Ichijo
- Laboratory of Cell SignalingGraduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
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30
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Alevriadou BR, Patel A, Noble M, Ghosh S, Gohil VM, Stathopulos PB, Madesh M. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am J Physiol Cell Physiol 2021; 320:C465-C482. [PMID: 33296287 PMCID: PMC8260355 DOI: 10.1152/ajpcell.00502.2020] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Calcium (Ca2+) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca2+ concentration ([Ca2+]i). Mitochondrial Ca2+ uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and the mitochondrial pathway of apoptosis. Mitochondrial Ca2+ uptake occurs via the mitochondrial Ca2+ uniporter (MCU) complex. This review summarizes the present knowledge on the function of MCU complex, regulation of MCU channel, and the role of MCU in Ca2+ homeostasis and human disease pathogenesis. The channel core consists of four MCU subunits and essential MCU regulators (EMRE). Regulatory proteins that interact with them include mitochondrial Ca2+ uptake 1/2 (MICU1/2), MCU dominant-negative β-subunit (MCUb), MCU regulator 1 (MCUR1), and solute carrier 25A23 (SLC25A23). In addition to these proteins, cardiolipin, a mitochondrial membrane-specific phospholipid, has been shown to interact with the channel core. The dynamic interplay between the core and regulatory proteins modulates MCU channel activity after sensing local changes in [Ca2+]i, reactive oxygen species, and other environmental factors. Here, we highlight the structural details of the human MCU heteromeric assemblies and their known roles in regulating mitochondrial Ca2+ homeostasis. MCU dysfunction has been shown to alter mitochondrial Ca2+ dynamics, in turn eliciting cell apoptosis. Changes in mitochondrial Ca2+ uptake have been implicated in pathological conditions affecting multiple organs, including the heart, skeletal muscle, and brain. However, our structural and functional knowledge of this vital protein complex remains incomplete, and understanding the precise role for MCU-mediated mitochondrial Ca2+ signaling in disease requires further research efforts.
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Affiliation(s)
- B Rita Alevriadou
- Department of Biomedical Engineering, Jacobs School of Medicine and Biomedical Sciences and School of Engineering and Applied Sciences, University at Buffalo-State University of New York, Buffalo, New York
| | - Akshar Patel
- Department of Biomedical Engineering, Jacobs School of Medicine and Biomedical Sciences and School of Engineering and Applied Sciences, University at Buffalo-State University of New York, Buffalo, New York
| | - Megan Noble
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Sagnika Ghosh
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
| | - Vishal M Gohil
- Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas
| | - Peter B Stathopulos
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
| | - Muniswamy Madesh
- Department of Medicine/Cardiology Division, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, Texas
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31
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Panda S, Behera S, Alam MF, Syed GH. Endoplasmic reticulum & mitochondrial calcium homeostasis: The interplay with viruses. Mitochondrion 2021; 58:227-242. [PMID: 33775873 DOI: 10.1016/j.mito.2021.03.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 03/08/2021] [Accepted: 03/22/2021] [Indexed: 02/08/2023]
Abstract
Calcium ions (Ca2+) act as secondary messengers in a plethora of cellular processes and play crucial role in cellular organelle function and homeostasis. The average resting concentration of Ca2+ is nearly 100 nM and in certain cells it can reach up to 1 µM. The high range of Ca2+ concentration across the plasma membrane and intracellular Ca2+ stores demands a well-coordinated maintenance of free Ca2+ via influx, efflux, buffering and storage. Endoplasmic Reticulum (ER) and Mitochondria depend on Ca2+ for their function and also serve as major players in intracellular Ca2+ homeostasis. The ER-mitochondria interplay helps in orchestrating cellular calcium homeostasis to avoid any detrimental effect resulting from Ca2+ overload or depletion. Since Ca2+ plays a central role in many biological processes it is an essential component of the virus-host interactions. The large gradient across membranes enable the viruses to easily modulate this buffered environment to meet their needs. Viruses exploit Ca2+ signaling to establish productive infection and evade the host immune defense. In this review we will detail the interplay between the viruses and cellular & ER-mitochondrial calcium signaling and the significance of these events on viral life cycle and disease pathogenesis.
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Affiliation(s)
- Swagatika Panda
- Institute of Life Sciences, Bhubaneswar, Virus-Host Interaction Lab, Institute of Life Sciences, Bhubaneswar, India
| | - Suchismita Behera
- Institute of Life Sciences, Bhubaneswar, Clinical Proteomics Laboratory, Institute of Life Sciences, Bhubaneswar, India
| | - Mohd Faraz Alam
- Institute of Life Sciences, Bhubaneswar, Virus-Host Interaction Lab, Institute of Life Sciences, Bhubaneswar, India
| | - Gulam Hussain Syed
- Institute of Life Sciences, Bhubaneswar, Virus-Host Interaction Lab, Institute of Life Sciences, Bhubaneswar, India.
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32
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Abstract
Mitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca2+ is a key modulator of both ATP production and cell death. Although mitochondrial Ca2+ uptake and efflux have been studied for over 50 years, it is only in the past decade that the proteins responsible for mitochondrial Ca2+ uptake and efflux have been identified. The identification of the mitochondrial Ca2+ uniporter (MCU) led to an explosion of studies identifying regulators of the MCU. The levels of these regulators vary in a tissue- and disease-specific manner, providing new insight into how mitochondrial Ca2+ is regulated. This review focuses on the proteins responsible for mitochondrial transport and what we have learned from mouse studies with genetic alterations in these proteins.
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Affiliation(s)
- Elizabeth Murphy
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
| | - Charles Steenbergen
- Department of Pathology, Johns Hopkins Medicine, Baltimore, Maryland 21287, USA
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33
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Madreiter-Sokolowski CT, Gottschalk B, Sokolowski AA, Malli R, Graier WF. Dynamic Control of Mitochondrial Ca 2+ Levels as a Survival Strategy of Cancer Cells. Front Cell Dev Biol 2021; 9:614668. [PMID: 33614647 PMCID: PMC7889948 DOI: 10.3389/fcell.2021.614668] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer cells have increased energy requirements due to their enhanced proliferation activity. This energy demand is, among others, met by mitochondrial ATP production. Since the second messenger Ca2+ maintains the activity of Krebs cycle dehydrogenases that fuel mitochondrial respiration, proper mitochondrial Ca2+ uptake is crucial for a cancer cell survival. However, a mitochondrial Ca2+ overload induces mitochondrial dysfunction and, ultimately, apoptotic cell death. Because of the vital importance of balancing mitochondrial Ca2+ levels, a highly sophisticated machinery of multiple proteins manages mitochondrial Ca2+ homeostasis. Notably, mitochondria sequester Ca2+ preferentially at the interaction sites between mitochondria and the endoplasmic reticulum (ER), the largest internal Ca2+ store, thus, pointing to mitochondrial-associated membranes (MAMs) as crucial hubs between cancer prosperity and cell death. To investigate potential regulatory mechanisms of the mitochondrial Ca2+ uptake routes in cancer cells, we modulated mitochondria-ER tethering and the expression of UCP2 and analyzed mitochondrial Ca2+ homeostasis under the various conditions. Hence, the expression of contributors to mitochondrial Ca2+ regulation machinery was quantified by qRT-PCR. We further used data from The Cancer Genome Atlas (TCGA) to correlate these in vitro findings with expression patterns in human breast invasive cancer and human prostate adenocarcinoma. ER-mitochondrial linkage was found to support a mitochondrial Ca2+ uptake route dependent on uncoupling protein 2 (UCP2) in cancer cells. Notably, combined overexpression of Rab32, a protein kinase A-anchoring protein fostering the ER-mitochondrial tethering, and UCP2 caused a significant drop in cancer cells' viability. Artificially enhanced ER-mitochondrial tethering further initiated a sudden decline in the expression of UCP2, probably as an adaptive response to avoid mitochondrial Ca2+ overload. Besides, TCGA analysis revealed an inverse expression correlation between proteins stabilizing mitochondrial-ER linkage and UCP2 in tissues of human breast invasive cancer and prostate adenocarcinoma. Based on these results, we assume that cancer cells successfully manage mitochondrial Ca2+ uptake to stimulate Ca2+-dependent mitochondrial metabolism while avoiding Ca2+-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner. Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells.
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Affiliation(s)
- Corina T. Madreiter-Sokolowski
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland
| | - Benjamin Gottschalk
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Armin A. Sokolowski
- Department of Dental Medicine and Oral Health, Medical University of Graz, Graz, Austria
| | - Roland Malli
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Wolfgang F. Graier
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
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34
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Li H, Wang C, Li L, Li L. Skeletal muscle non-shivering thermogenesis as an attractive strategy to combat obesity. Life Sci 2021; 269:119024. [PMID: 33450257 DOI: 10.1016/j.lfs.2021.119024] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/05/2023]
Abstract
Obesity is a chronic disease derived from disequilibrium between energy intake and energy expenditure and evolving as a challenging epidemiological disease in the 21st century. It is urgently necessary to solve this issue by searching for effective strategies and safe drugs. Skeletal muscle could be a potential therapeutic target for the prevention and treatment of obesity and its associated complications due to non-shivering thermogenesis (NST) function. Skeletal muscle NST is based dominantly on futile sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump cycling that leads to a rise in cytosolic Ca2+, increased adenosine triphosphate (ATP) hydrolysis and heat production. This review will highlight the mechanisms of skeletal muscle NST, including SLN mediated SERCA pump futile cycling, SR-mitochondrial crosstalk and increased mitochondrial biogenesis, and thermogenesis induced by uncoupling proteins 3 (UCP3). We then summarize natural products targeting the pathogenesis of obesity via skeletal muscle NST, offering new insights into pharmacotherapy and potential drug candidates to combat obesity.
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Affiliation(s)
- Hanbing Li
- Institute of Pharmacology, Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China; Section of Endocrinology, School of Medicine, Yale University, New Haven 06520, USA.
| | - Can Wang
- Institute of Pharmacology, Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Linghuan Li
- Institute of Pharmacology, Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
| | - Lingqiao Li
- Zhejiang Starry Pharmaceutical Co., Ltd., Taizhou 317306, PR China
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35
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Ardalan A, Sowlati-Hashjin S, Uwumarenogie SO, Fish M, Mitchell J, Karttunen M, Smith MD, Jelokhani-Niaraki M. Functional Oligomeric Forms of Uncoupling Protein 2: Strong Evidence for Asymmetry in Protein and Lipid Bilayer Systems. J Phys Chem B 2020; 125:169-183. [PMID: 33373220 DOI: 10.1021/acs.jpcb.0c09422] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Stoichiometry of uncoupling proteins (UCPs) and their coexistence as functional monomeric and associated forms in lipid membranes remain intriguing open questions. In this study, tertiary and quaternary structures of UCP2 were analyzed experimentally and through molecular dynamics (MD) simulations. UCP2 was overexpressed in the inner membrane of Escherichia coli, then purified and reconstituted in lipid vesicles. Structure and proton transport function of UCP2 were characterized by circular dichroism (CD) spectroscopy and fluorescence methods. Findings suggest a tetrameric functional form for UCP2. MD simulations conclude that tetrameric UCP2 is a dimer of dimers, is more stable than its monomeric and dimeric forms, is asymmetrical and induces asymmetry in the membrane's lipid structure, and a biphasic on-off switch between the dimeric units is its possible mode of transport. MD simulations also show that the water density inside the UCP2 monomer is asymmetric, with the cytoplasmic side having a higher water density and a wider radius. In contrast, the structurally comparable adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier (AAC1) did not form tetramers, implying that tetramerization cannot be generalized to all mitochondrial carriers.
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Affiliation(s)
- Afshan Ardalan
- Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
| | - Shahin Sowlati-Hashjin
- Department of Chemistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7.,Center for Advanced Materials and Biomaterials Research, The University of Western Ontario, London, Ontario, Canada N6K 3K7
| | - Stephanie O Uwumarenogie
- Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
| | - Michael Fish
- Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5.,Department of Biology, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
| | - Joel Mitchell
- Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
| | - Mikko Karttunen
- Department of Chemistry, The University of Western Ontario, London, Ontario, Canada N6A 3K7.,Center for Advanced Materials and Biomaterials Research, The University of Western Ontario, London, Ontario, Canada N6K 3K7.,Department of Applied Mathematics, The University of Western Ontario, London, Ontario, Canada N6A 5B7
| | - Matthew D Smith
- Department of Biology, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
| | - Masoud Jelokhani-Niaraki
- Department of Chemistry and Biochemistry, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5
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36
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Koshenov Z, Oflaz FE, Hirtl M, Bachkoenig OA, Rost R, Osibow K, Gottschalk B, Madreiter-Sokolowski CT, Waldeck-Weiermair M, Malli R, Graier WF. The contribution of uncoupling protein 2 to mitochondrial Ca 2+ homeostasis in health and disease - A short revisit. Mitochondrion 2020; 55:164-173. [PMID: 33069910 DOI: 10.1016/j.mito.2020.10.003] [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: 07/23/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 12/18/2022]
Abstract
Considering the versatile functions attributed to uncoupling protein 2 (UCP2) in health and disease, a profound understanding of the protein's molecular actions under physiological and pathophysiological conditions is indispensable. This review aims to revisit and shed light on the fundamental molecular functions of UCP2 in mitochondria, with particular emphasis on its intricate role in regulating mitochondrial calcium (Ca2+) uptake. UCP2's modulating effect on various vital processes in mitochondria makes it a crucial regulator of mitochondrial homeostasis in health and disease.
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Affiliation(s)
- Zhanat Koshenov
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Furkan E Oflaz
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Martin Hirtl
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Olaf A Bachkoenig
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Rene Rost
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Karin Osibow
- Diagnostic and Research Institute for Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria; Department of Health Sciences and Technology, ETH Zurich, Schorenstraße 16, 8603 Schwerzenbach, Switzerland
| | - Benjamin Gottschalk
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
| | - Corina T Madreiter-Sokolowski
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; Diagnostic and Research Institute for Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
| | - Markus Waldeck-Weiermair
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Roland Malli
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; BioTechMed, Graz, Austria
| | - Wolfgang F Graier
- Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; BioTechMed, Graz, Austria.
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Mitochondria-lysosome contacts regulate mitochondrial Ca 2+ dynamics via lysosomal TRPML1. Proc Natl Acad Sci U S A 2020; 117:19266-19275. [PMID: 32703809 DOI: 10.1073/pnas.2003236117] [Citation(s) in RCA: 192] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
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38
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Cunningham CN, Rutter J. 20,000 picometers under the OMM: diving into the vastness of mitochondrial metabolite transport. EMBO Rep 2020; 21:e50071. [PMID: 32329174 DOI: 10.15252/embr.202050071] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/17/2020] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
The metabolic compartmentalization enabled by mitochondria is key feature of many cellular processes such as energy conversion to ATP production, redox balance, and the biosynthesis of heme, urea, nucleotides, lipids, and others. For a majority of these functions, metabolites need to be transported across the impermeable inner mitochondrial membrane by dedicated carrier proteins. Here, we examine the substrates, structural features, and human health implications of four mitochondrial metabolite carrier families: the SLC25A family, the mitochondrial ABCB transporters, the mitochondrial pyruvate carrier (MPC), and the sideroflexin proteins.
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Affiliation(s)
- Corey N Cunningham
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA.,Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
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Ca (2+)N It Be Measured? Detection of Extramitochondrial Calcium Movement With High-Resolution FluoRespirometry. Sci Rep 2019; 9:19229. [PMID: 31848391 PMCID: PMC6917783 DOI: 10.1038/s41598-019-55618-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/13/2019] [Indexed: 11/24/2022] Open
Abstract
Our aim was to develop a method to detect extramitochondrial Ca2+ movement and O2 fluxes simultaneously. Using High-Resolution FluoRespirometry, we also tested whether mitochondrial permeability transition pore (mPTP) inhibition or anoxia affects the mitochondrial Ca2+ flux. Ca2+ movement evoked by CaCl2 or anoxia was assessed with CaGreen-5N dye using Blue-Fluorescence-Sensor in isolated liver mitochondria, liver homogenates and duodenal biopsies. Exogenous CaCl2 (50 µM) resulted in an abrupt elevation in CaGreen-5N fluorescence followed by a decrease (Ca2+ uptake) with simultaneous elevation in O2 consumption in liver preparations. This was followed by a rapid increase in the fluorescence signal, reaching a higher intensity (Ca2+ efflux) than that of the initial CaCl2-induced elevation. Chelation of Ca2+ with EGTA completely abolished the fluorescence of the indicator. After pre-incubation with cyclosporin A, a marked delay in Ca2+ movement was observed, not only in isolated liver mitochondria, but also in tissue homogenates. In all samples, the transition to anoxia resulted in immediate increase in the level of extramitochondrial Ca2+. The results demonstrate that the CaGreen-5N method is suitable to monitor simultaneous O2 and Ca2+ fluxes, and the opening of mPTP in various biological samples. In this system the duration of stimulated Ca2+ fluxes may provide a novel parameter to evaluate the efficacy of mPTP blocker compounds.
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40
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Tarasova NV, Vishnyakova PA, Logashina YA, Elchaninov AV. Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease. Int J Mol Sci 2019; 20:ijms20194823. [PMID: 31569359 PMCID: PMC6801532 DOI: 10.3390/ijms20194823] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/12/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023] Open
Abstract
Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease.
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Affiliation(s)
- Nadezhda V Tarasova
- Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Trubetskaya str. 8, bld. 2, Moscow 119991, Russia.
| | - 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 Street, Moscow 117997, Russia.
| | - Yulia A Logashina
- Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Trubetskaya str. 8, bld. 2, Moscow 119991, Russia.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, Moscow 117997, Russia.
| | - Andrey V Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Scientific Research Institute of Human Morphology, 3 Tsurupa Street, Moscow 117418, Russia.
- Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
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41
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Chen YF, Dugas TR. Endothelial mitochondrial senescence accelerates cardiovascular disease in antiretroviral-receiving HIV patients. Toxicol Lett 2019; 317:13-23. [PMID: 31562912 DOI: 10.1016/j.toxlet.2019.09.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/12/2019] [Accepted: 09/21/2019] [Indexed: 02/06/2023]
Abstract
Combination antiretroviral therapy (cART) has been hugely successful in reducing the mortality associated with human immunodeficiency virus (HIV) infection, resulting in a growing population of people living with HIV (PLWH). Since PLWH now have a longer life expectancy, chronic comorbidities have become the focus of the clinical management of HIV. For example, cardiovascular complications are now one of the most prevalent causes of death in PLWH. Numerous epidemiological studies show that antiretroviral treatment increases cardiovascular disease (CVD) risk and early onset of CVD in PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and two NRTIs are typically used in combination with one drug from another drug class, e.g., a fusion inhibitor. NRTIs are known to induce mitochondrial dysfunction, contributing to toxicity in numerous tissues, such as myopathy, lipoatrophy, neuropathy, and nephropathy. In in vitro studies, short-term NRTI treatment induces an endothelial dysfunction with an increased reactive oxygen species (ROS) production; long-term NRTI treatment decreases cell replication capacity, while increasing mtROS production and senescent cell accumulation. These findings suggest that a mitochondrial oxidative stress is involved in the pathogenesis of NRTI-induced endothelial dysfunction and premature senescence. Mitochondrial dysfunction, defined by a compromised mitochondrial quality control via biogenesis and mitophagy, has a causal role in premature endothelial senescence and can potentially initiate early cardiovascular disease (CVD) development in PLWH. In this review, we explore the hypothesis and present literature supporting that long-term NRTI treatment induces vascular dysfunction by interfering with endothelial mitochondrial homeostasis and provoking mitochondrial genomic instability, resulting in premature endothelial senescence.
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Affiliation(s)
- Yi-Fan Chen
- Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, LA, 70808, United States
| | - Tammy R Dugas
- Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, LA, 70808, United States.
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42
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Gottschalk B, Klec C, Leitinger G, Bernhart E, Rost R, Bischof H, Madreiter-Sokolowski CT, Radulović S, Eroglu E, Sattler W, Waldeck-Weiermair M, Malli R, Graier WF. MICU1 controls cristae junction and spatially anchors mitochondrial Ca 2+ uniporter complex. Nat Commun 2019; 10:3732. [PMID: 31427612 PMCID: PMC6700202 DOI: 10.1038/s41467-019-11692-x] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 07/30/2019] [Indexed: 12/15/2022] Open
Abstract
Recently identified core proteins (MICU1, MCU, EMRE) forming the mitochondrial Ca2+ uniporter complex propelled investigations into its physiological workings. Here, we apply structured illumination microscopy to visualize and localize these proteins in living cells. Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. Moreover, this exclusive localization of MICU1 is important for the stability of cristae junctions (CJ), cytochrome c release and mitochondrial membrane potential. In contrast to MICU1, MCU and EMRE are homogeneously distributed at the inner mitochondrial membrane under resting conditions. However, upon Ca2+ elevation MCU and EMRE dynamically accumulate at the IBM in a MICU1-dependent manner. Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework.
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Affiliation(s)
- Benjamin Gottschalk
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Christiane Klec
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Gerd Leitinger
- Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, Neue Stiftingtalstraße 6/2, 8010, Graz, Austria
| | - Eva Bernhart
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - René Rost
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Helmut Bischof
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Corina T Madreiter-Sokolowski
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Snježana Radulović
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
- Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, Neue Stiftingtalstraße 6/2, 8010, Graz, Austria
| | - Emrah Eroglu
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Wolfgang Sattler
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
- BioTechMed Graz, Mozartgasse 12/2, Graz, 8010, Austria
| | - Markus Waldeck-Weiermair
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
| | - Roland Malli
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria
- BioTechMed Graz, Mozartgasse 12/2, Graz, 8010, Austria
| | - Wolfgang F Graier
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010, Graz, Austria.
- BioTechMed Graz, Mozartgasse 12/2, Graz, 8010, Austria.
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Pohl EE, Rupprecht A, Macher G, Hilse KE. Important Trends in UCP3 Investigation. Front Physiol 2019; 10:470. [PMID: 31133866 PMCID: PMC6524716 DOI: 10.3389/fphys.2019.00470] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Accepted: 04/04/2019] [Indexed: 11/13/2022] Open
Abstract
Membrane uncoupling protein 3 (UCP3), a member of the mitochondrial uncoupling protein family, was discovered in 1997. UCP3's properties, such as its high homology to other mitochondrial carriers, especially to UCP2, its short lifetime and low specificity of UCP3 antibodies, have hindered progress in understanding its biological function and transport mechanism over decades. The abundance of UCP3 is highest in murine brown adipose tissue (BAT, 15.0 pmol/mg protein), compared to heart (2.7 pmol/mg protein) and the gastrocnemius muscle (1.7 pmol/mg protein), but it is still 400-fold lower than the abundance of UCP1, a biomarker for BAT. Investigation of UCP3 reconstituted in planar bilayer membranes revealed that it transports protons only when activated by fatty acids (FA). Although purine nucleotides (PN) inhibit UCP3-mediated transport, the molecular mechanism differs from that of UCP1. It remains a conundrum that two homologous proton-transporting proteins exist within the same tissue. Recently, we proposed that UCP3 abundance directly correlates with the degree of FA β-oxidation in cell metabolism. Further development in this field implies that UCP3 may have dual function in transporting substrates, which have yet to be identified, alongside protons. Evaluation of the literature with respect to UCP3 is a complex task because (i) UCP3 features are often extrapolated from its "twin" UCP2 without additional proof, and (ii) the specificity of antibodies against UCP3 used in studies is rarely evaluated. In this review, we primarily focus on recent findings obtained for UCP3 in biological and biomimetic systems.
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Affiliation(s)
- Elena E. Pohl
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
| | - Anne Rupprecht
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Gabriel Macher
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
| | - Karolina E. Hilse
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria
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De la Fuente S, Sheu SS. SR-mitochondria communication in adult cardiomyocytes: A close relationship where the Ca 2+ has a lot to say. Arch Biochem Biophys 2019; 663:259-268. [PMID: 30685253 PMCID: PMC6377816 DOI: 10.1016/j.abb.2019.01.026] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 01/14/2019] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
In adult cardiomyocytes, T-tubules, junctional sarcoplasmic reticulum (jSR), and mitochondria juxtapose each other and form a unique and highly repetitive functional structure along the cell. The close apposition between jSR and mitochondria creates high Ca2+ microdomains at the contact sites, increasing the efficiency of the excitation-contraction-bioenergetics coupling, where the Ca2+ transfer from SR to mitochondria plays a critical role. The SR-mitochondria contacts are established through protein tethers, with mitofusin 2 the most studied SR-mitochondrial "bridge", albeit controversial. Mitochondrial Ca2+ uptake is further optimized with the mitochondrial Ca2+ uniporter preferentially localized in the jSR-mitochondria contact sites and the mitochondrial Na+/Ca2+ exchanger localized away from these sites. Despite all these unique features facilitating the privileged transport of Ca2+ from SR to mitochondria in adult cardiomyocytes, the question remains whether mitochondrial Ca2+ concentrations oscillate in synchronicity with cytosolic Ca2+ transients during heartbeats. Proper Ca2+ transfer controls not only the process of mitochondrial bioenergetics, but also of mitochondria-mediated cell death, autophagy/mitophagy, mitochondrial fusion/fission dynamics, reactive oxygen species generation, and redox signaling, among others. Our review focuses specifically on Ca2+ signaling between SR and mitochondria in adult cardiomyocytes. We discuss the physiological and pathological implications of this SR-mitochondrial Ca2+ signaling, research gaps, and future trends.
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Affiliation(s)
- Sergio De la Fuente
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
| | - Shey-Shing Sheu
- Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
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45
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Samanta K, Bakowski D, Amin N, Parekh AB. The whole-cell Ca 2+ release-activated Ca 2+ current, I CRAC , is regulated by the mitochondrial Ca 2+ uniporter channel and is independent of extracellular and cytosolic Na . J Physiol 2019;598:1753-1773. [PMID: 30582626 PMCID: PMC7318671 DOI: 10.1113/jp276551] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 12/05/2018] [Indexed: 12/12/2022] Open
Abstract
Key points
Ca2+ entry through Ca2+ release‐activated Ca2+ channels activates numerous cellular responses. Under physiological conditions of weak intracellular Ca2+ buffering, mitochondrial Ca2+ uptake regulates CRAC channel activity. Knockdown of the mitochondrial Ca2+ uniporter channel prevented the development of ICRAC in weak buffer but not when strong buffer was used instead. Removal of either extracellular or intra‐pipette Na+ had no effect on the selectivity, kinetics, amplitude, rectification or reversal potential of whole‐cell CRAC current. Knockdown of the mitochondrial Na+–Ca2+ exchanger did not prevent the development of ICRAC in strong or weak Ca2+ buffer. Whole cell CRAC current is Ca2+‐selective. Mitochondrial Ca2+ channels, and not Na+‐dependent transport, regulate CRAC channels under physiological conditions. Abstract Ca2+ entry through store‐operated Ca2+ release‐activated Ca2+ (CRAC) channels plays a central role in activation of a range of cellular responses over broad spatial and temporal bandwidths. Mitochondria, through their ability to take up cytosolic Ca2+, are important regulators of CRAC channel activity under physiological conditions of weak intracellular Ca2+ buffering. The mitochondrial Ca2+ transporter(s) that regulates CRAC channels is unclear and could involve the 40 kDa mitochondrial Ca2+ uniporter (MCU) channel or the Na+–Ca2+–Li+ exchanger (NCLX). Here, we have investigated the involvement of these mitochondrial Ca2+ transporters in supporting the CRAC current (ICRAC) under a range of conditions in RBL mast cells. Knockdown of the MCU channel impaired the activation of ICRAC under physiological conditions of weak intracellular Ca2+ buffering. In strong Ca2+ buffer, knockdown of the MCU channel did not inhibit ICRAC development demonstrating that mitochondria regulate CRAC channels under physiological conditions by buffering of cytosolic Ca2+ via the MCU channel. Surprisingly, manipulations that altered extracellular Na+, cytosolic Na+ or both failed to inhibit the development of ICRAC in either strong or weak intracellular Ca2+ buffer. Knockdown of NCLX also did not affect ICRAC. Prolonged removal of external Na+ also had no significant effect on store‐operated Ca2+ entry, on cytosolic Ca2+ oscillations generated by receptor stimulation or on CRAC channel‐driven gene expression. In the RBL mast cell, Ca2+ flux through the MCU but not NCLX is indispensable for activation of ICRAC.
Ca2+ entry through Ca2+ release‐activated Ca2+ channels activates numerous cellular responses. Under physiological conditions of weak intracellular Ca2+ buffering, mitochondrial Ca2+ uptake regulates CRAC channel activity. Knockdown of the mitochondrial Ca2+ uniporter channel prevented the development of ICRAC in weak buffer but not when strong buffer was used instead. Removal of either extracellular or intra‐pipette Na+ had no effect on the selectivity, kinetics, amplitude, rectification or reversal potential of whole‐cell CRAC current. Knockdown of the mitochondrial Na+–Ca2+ exchanger did not prevent the development of ICRAC in strong or weak Ca2+ buffer. Whole cell CRAC current is Ca2+‐selective. Mitochondrial Ca2+ channels, and not Na+‐dependent transport, regulate CRAC channels under physiological conditions.
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Affiliation(s)
- Krishna Samanta
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK
| | - Daniel Bakowski
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK
| | - Nader Amin
- Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
| | - Anant B Parekh
- Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK
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Wang X, Liu X, Ren Y, Liu Y, Han S, Zhao J, Gou X, He Y. PEDF protects human retinal pigment epithelial cells against oxidative stress via upregulation of UCP2 expression. Mol Med Rep 2018; 19:59-74. [PMID: 30431098 PMCID: PMC6297793 DOI: 10.3892/mmr.2018.9645] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 09/07/2018] [Indexed: 01/23/2023] Open
Abstract
To investigate the protective function of pigment epithelium-derived factor (PEDF) against oxidative stress (OS) in ARPE-19 cells, ARPE-19 cells were divided into different OS groups and treated with various concentrations of H2O2 (0, 75, 150 and 200 µmol/l) for 24 h. To establish the protective group, 200 ng/ml of PEDF was administered to ARPE-19 cells. Cell Counting Kit-8 assays and cell growth curve experiments were performed to determine levels of cell viability; lactate dehydrogenase and propidium iodide (PI) staining assays were also performed. The expression levels of genes associated with apoptosis as well as uncoupling protein 2 (UCP2) were detected by reverse transcription-quantitative, or semi-quantitative polymerase chain reaction. Furthermore, an OS injury animal model was established in both C57BL/6 and BALB/c mice via injection of 5 µg of PEDF in the vitreous cavity and subsequent injection of 150 µM H2O2 following a 24 h time interval. Hematoxylin and eosin (H&E) staining, as well as UCP2 immunofluorescent labeling were also performed. One-way analysis of variance was used to determine statistically significant differences, followed by multiple comparison analysis using the Newman Keuls method. The results of cell viability assays demonstrated that the numbers of apoptotic cells were increased following treatment with H2O2 in a dose-dependent manner; however, this effect was reversed following treatment with PEDF. The expression levels of caspase 3 and B cell lymphoma (Bcl2) associated X genes associated with apoptosis were inhibited, whereas levels of the anti-apoptotic gene Bcl2 were enhanced following treatment with PEDF in different passages of ARPE-19 cells. Significant differences were demonstrated in the levels of UCP2 gene expression between the PEDF+ H2O2 treated group and cells treated with H2O2 alone. Labeling of the UCP2 detector in the confocal images demonstrated decreased UCP2 protein staining in the retinal pigment epithelium (RPE) cells and RPE layers following H2O2 injury; however, this effect was inhibited following treatment with PEDF. H&E staining was performed to investigate the thickness of the RPE layers, and the results revealed that thicknesses were significantly increased in sections treated with PEDF during OS, due to increased numbers of RPE cells. Furthermore, PEDF was demonstrated to increase UCP2 gene expression in ARPE-19 cells and animal RPE layers under OS, which suggested that PEDF may protect RPE cells and tissues during oxidative injury.
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Affiliation(s)
- Xia Wang
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Xu Liu
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Yuan Ren
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Ying Liu
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Shuangyu Han
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Jingkang Zhao
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
| | - Xingchun Gou
- Department of Neurobiology, The Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Yuan He
- Department of Ophthalmology, The Second Affiliated Hospital of Xi'an Medical University, Ocular Immunology and Inflammation Institute, Shaanxi Provincial Clinical Research Center for Ophthalmology, Xi'an, Shaanxi 710038, P.R. China
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Ježek P, Holendová B, Garlid KD, Jabůrek M. Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxid Redox Signal 2018; 29:667-714. [PMID: 29351723 PMCID: PMC6071544 DOI: 10.1089/ars.2017.7225] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
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Affiliation(s)
- Petr Ježek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Blanka Holendová
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Keith D Garlid
- 2 UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Martin Jabůrek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
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Cadenas S. Mitochondrial uncoupling, ROS generation and cardioprotection. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2018; 1859:940-950. [DOI: 10.1016/j.bbabio.2018.05.019] [Citation(s) in RCA: 238] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/11/2018] [Accepted: 05/29/2018] [Indexed: 12/31/2022]
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Giorgi C, Marchi S, Pinton P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol 2018; 19:713-730. [PMID: 30143745 DOI: 10.1038/s41580-018-0052-8] [Citation(s) in RCA: 555] [Impact Index Per Article: 79.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.
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Affiliation(s)
- Carlotta Giorgi
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Saverio Marchi
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy. .,Maria Cecilia Hospital, GVM Care and Research, Cotignola, Ravenna, Italy.
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Tian XY, Ma S, Tse G, Wong WT, Huang Y. Uncoupling Protein 2 in Cardiovascular Health and Disease. Front Physiol 2018; 9:1060. [PMID: 30116205 PMCID: PMC6082951 DOI: 10.3389/fphys.2018.01060] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 07/16/2018] [Indexed: 12/22/2022] Open
Abstract
Uncoupling protein 2 (UCP2) belongs to the family of mitochondrial anion carrier proteins. It uncouples oxygen consumption from ATP synthesis. UCP2 is ubiquitously expressed in most cell types to reduce oxidative stress. It is tightly regulated at the transcriptional, translational, and post-translational levels. UCP2 in the cardiovascular system is being increasingly recognized as an important molecule to defend against various stress signals such as oxidative stress in the pathology of vascular dysfunction, atherosclerosis, hypertension, and cardiac injuries. UCP2 protects against cellular dysfunction through reducing mitochondrial oxidative stress and modulation of mitochondrial function. In view of the different functions of UCP2 in various cell types that contribute to whole body homeostasis, cell type-specific modification of UCP2 expression may offer a better approach to help understanding how UCP2 governs mitochondrial function, reactive oxygen species production and transmembrane proton leak and how dysfunction of UCP2 participates in the development of cardiovascular diseases. This review article provided an update on the physiological regulation of UCP2 in the cardiovascular system, and also discussed the involvement of UCP2 deficiency and associated oxidative stress in the pathogenesis of several common cardiovascular diseases. Drugs targeting UCP2 expression and activity might serve another effective strategy to ameliorate cardiovascular dysfunction. However, more detailed mechanistic study will be needed to dissect the role of UCP2, the regulation of UCP2 expression, and the cellular responses to the changes of UCP2 expression in normal and stressed situations at different stages of cardiovascular diseases.
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Affiliation(s)
- Xiao Yu Tian
- School of Biomedical Sciences, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Shuangtao Ma
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI, United States
| | - Gary Tse
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Yu Huang
- School of Biomedical Sciences, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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