Mitochondrial Calcium Uptake in Activation of the Permeability Transition Pore and Cell Death

2017 ◽  
pp. 107-118
Author(s):  
Maria E. Solesio ◽  
Evgeny V. Pavlov
Keyword(s):  
Cell Death ◽  
Calcium Uptake ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uptake

scholarly journals Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death

2020 ◽  
Vol 126 (2) ◽  
pp. 280-293 ◽  
Author(s):  
Tyler M. Bauer ◽  
Elizabeth Murphy
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Calcium ◽  
Oxygen Species ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Cell Death Pathways

Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

scholarly journals Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death

2016 ◽  
Vol 126 (9) ◽  
pp. 3556-3566 ◽  
Author(s):  
Robert Esterberg ◽  
Tor Linbo ◽  
Sarah B. Pickett ◽  
Patricia Wu ◽  
Henry C. Ou ◽  
...  
Keyword(s):  
Cell Death ◽  
Hair Cell ◽  
Calcium Uptake ◽  
Ros Generation ◽  
Mitochondrial Calcium ◽  
Hair Cell Death ◽  
Mitochondrial Calcium Uptake

scholarly journals Mitochondrial calcium signalling and neurodegenerative diseases

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Elena Britti ◽  
Fabien Delaspre ◽  
Jordi Tamarit ◽  
Joaquim Ros
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Friedreich Ataxia ◽  
Calcium Signalling ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytosolic Calcium ◽  
Mitochondrial Calcium ◽  
Atp Production ◽  
Calcium Buffering ◽  
Mitochondrial Calcium Uptake

Calcium is utilised by cells in signalling and in regulating ATP production; it also contributes to cell survival and, when concentrations are unbalanced, triggers pathways for cell death. Mitochondria contribute to calcium buffering, meaning that mitochondrial calcium uptake and release is intimately related to cytosolic calcium concentrations. This review focuses on the proteins contributing to mitochondrial calcium homoeostasis, the roles of the mitochondrial permeability transition pore (MPTP) and mitochondrial calcium-activated proteins, and their relevance in neurodegenerative pathologies. It also covers alterations to calcium homoeostasis in Friedreich ataxia (FA).

scholarly journals The Valosin-Containing Protein Protects the Heart Against Pathological Ca2+ Overload by Modulating Ca2+ Uptake Proteins

2019 ◽  
Vol 171 (2) ◽  
pp. 473-484 ◽  
Author(s):  
Shaunrick Stoll ◽  
Jing Xi ◽  
Ben Ma ◽  
Christiana Leimena ◽  
Erik J Behringer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Calcium ◽  
Mptp Opening ◽  
Mitochondrial Calcium Uptake

Abstract Stress-induced mitochondrial calcium (Ca2+) overload is a key cellular toxic effectors and a trigger of cardiomyocyte death during cardiac ischemic injury through the opening of mitochondrial permeability transition pore (mPTP). We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP acts as a novel regulator of mitochondrial Ca2+ uptake proteins and resists cardiac mitochondrial Ca2+ overload by modulating mitochondrial Ca2+ homeostasis. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the heart compared to the wild type (WT) mouse, we found that, under the pathological extra-mitochondrial Ca2+ overload, Ca2+ entry into cardiac mitochondria was reduced in VCP TG mice compared to their little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca2+ challenge. Mechanistically, overexpression of VCP in the heart resulted in post-translational protein degradation of the mitochondrial Ca2+ uptake protein 1, an activator of the mitochondria Ca2+ uniporter that is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca2+ homeostasis and unlock the potential mechanism by which VCP confers its cardioprotection.

scholarly journals Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation

2013 ◽  
Vol 289 (3) ◽  
pp. 1491-1504 ◽  
Author(s):  
Bogeon Yun ◽  
HeeJung Lee ◽  
Moumita Ghosh ◽  
Benjamin F. Cravatt ◽  
Ku-Lung Hsu ◽  
...  
Keyword(s):  
Cell Death ◽  
Arachidonic Acid ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Necrotic Cell Death ◽  
Arachidonic Acid Release ◽  
Serine Hydrolase ◽  
Necrotic Cell ◽  
Acid Release ◽  
Mitochondrial Calcium Uptake

Perturbation of calcium signaling that occurs during cell injury and disease, promotes cell death. In mouse lung fibroblasts A23187 triggered mitochondrial permeability transition pore (MPTP) formation, lactate dehydrogenase (LDH) release, and necrotic cell death that were blocked by cyclosporin A (CsA) and EGTA. LDH release temporally correlated with arachidonic acid release but did not involve cytosolic phospholipase A2α (cPLA2α) or calcium-independent PLA2. Surprisingly, release of arachidonic acid and LDH from cPLA2α-deficient fibroblasts was inhibited by the cPLA2α inhibitor pyrrophenone, and another serine hydrolase inhibitor KT195, by preventing mitochondrial calcium uptake. Inhibitors of calcium/calmodulin-dependent protein kinase II, a mitochondrial Ca2+ uniporter (MCU) regulator, also prevented MPTP formation and arachidonic acid release induced by A23187 and H2O2. Pyrrophenone blocked MCU-mediated mitochondrial calcium uptake in permeabilized fibroblasts but not in isolated mitochondria. Unlike pyrrophenone, the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol and CsA blocked cell death and arachidonic acid release not by preventing mitochondrial calcium uptake but by inhibiting MPTP formation. In fibroblasts stimulated with thapsigargin, which induces MPTP formation by a direct effect on mitochondria, LDH and arachidonic acid release were blocked by CsA and 1-oleoyl-2-acetyl-sn-glycerol but not by pyrrophenone or EGTA. Therefore serine hydrolase inhibitors prevent necrotic cell death by blocking mitochondrial calcium uptake but not the enzyme releasing fatty acids that occurs by a novel pathway during MPTP formation. This work reveals the potential for development of small molecule cell-permeable serine hydrolase inhibitors that block MCU-mediated mitochondrial calcium overload, MPTP formation, and necrotic cell death.

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