scholarly journals Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition

2016 ◽  
Vol 113 (13) ◽  
pp. E1872-E1880 ◽  
Author(s):  
Dipayan Chaudhuri ◽  
Daniel J. Artiga ◽  
Sunday A. Abiria ◽  
David E. Clapham
Keyword(s):  
Mammalian Cells ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Permeability ◽  
Calcium Uniporter ◽  
Differential Behavior ◽  
Cardiac Pathophysiology ◽  
Large Channel

During the mitochondrial permeability transition, a large channel in the inner mitochondrial membrane opens, leading to the loss of multiple mitochondrial solutes and cell death. Key triggers include excessive reactive oxygen species and mitochondrial calcium overload, factors implicated in neuronal and cardiac pathophysiology. Examining the differential behavior of mitochondrial Ca2+ overload in Drosophila versus human cells allowed us to identify a gene, MCUR1, which, when expressed in Drosophila cells, conferred permeability transition sensitive to electrophoretic Ca2+ uptake. Conversely, inhibiting MCUR1 in mammalian cells increased the Ca2+ threshold for inducing permeability transition. The effect was specific to the permeability transition induced by Ca2+, and such resistance to overload translated into improved cell survival. Thus, MCUR1 expression regulates the Ca2+ threshold required for permeability transition.

Abstract 432: MCUB Regulates Mitochondrial Calcium Uniporter Channel Gating and Modulates Bioenergetics and Cell Death

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Jonathan P Lambert ◽  
TImothy S Luongo ◽  
Pooja Jadiya ◽  
Erhe Gao ◽  
Xueqian Zhang ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Channel Gating ◽  
High Capacity ◽  
Permeability Transition ◽  
Contractile Reserve ◽  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Retention Capacity ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter

The mitochondrial calcium uniporter (MCU) is a high-capacity, inward-rectifying channel in the inner mitochondrial membrane and is required for mitochondrial Ca 2+ ( m Ca 2+ ) uptake. m Ca 2+ signaling regulates bioenergetics and activates the mitochondrial permeability transition pore (MPTP) which are cellular processes implicated in cardiac pathophysiology warranting further research into the molecular regulation of the MCU. Recently, a MCU gene paralog, MCUB , was identified as a possible component of the channel. To investigate MCUB’s contribution to uniporter regulation we created a MCUB -/- HeLa cell line using CRISPR-Cas9n. Here, we report that loss of MCUB increased m Ca 2+ transient amplitude after IP3R stimulation (52% vs. con) suggesting MCUB negatively regulates m Ca 2+ uptake. Mitoplast patch-clamping confirmed that loss of MCUB increases MCU current density, suggesting MCUb modulates channel capacitance. Permeabilized MCUB -/- and WT cells exposed to various levels of Ca 2+ (0.5-20μM) revealed that MCUB -/- cells exhibited m Ca 2+ uptake at lower Ca 2+ concentrations than controls, suggesting MCUB contributes to channel gating. In m Ca 2+ retention capacity experiments MCUB -/- cells required ~30% less bath Ca 2+ to induce depolarization, suggesting a predisposition to m Ca 2+ overload. Next, we generated a cardiac-specific, tamoxifen-inducible MCUB overexpression mouse model ( MCUB -Tg). Cardiomyocytes isolated from MCUB -Tg hearts exhibited decreased m Ca 2+ uptake at low-Ca 2+ (59% vs. con) and isolated mitochondria exhibited a reduction in Ca 2+ -induced swelling (37% vs. con), suggesting a resistance to permeability transition. MCUB -Tg mice displayed a significant impairment in isoproterenol-induced contractile reserve and this correlated with a loss of isoproterenol-mediated activation of pyruvate dehydrogenase. In summary, our results suggest that MCUB limits m Ca 2+ uptake by altering channel-gating and thereby regulates bioenergetics and MPTP opening.

scholarly journals The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

2015 ◽  
Vol 95 (4) ◽  
pp. 1111-1155 ◽  
Author(s):  
Paolo Bernardi ◽  
Andrea Rasola ◽  
Michael Forte ◽  
Giovanna Lippe
Keyword(s):  
Signal Transduction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Pore Channel ◽  
Inner Mitochondrial Membrane ◽  
Electrophysiological Properties ◽  
Mitochondrial Permeability ◽  
Functional Features ◽  
Atp Synthases

The mitochondrial permeability transition (PT) is a permeability increase of the inner mitochondrial membrane mediated by a channel, the permeability transition pore (PTP). After a brief historical introduction, we cover the key regulatory features of the PTP and provide a critical assessment of putative protein components that have been tested by genetic analysis. The discovery that under conditions of oxidative stress the F-ATP synthases of mammals, yeast, and Drosophila can be turned into Ca2+-dependent channels, whose electrophysiological properties match those of the corresponding PTPs, opens new perspectives to the field. We discuss structural and functional features of F-ATP synthases that may provide clues to its transition from an energy-conserving into an energy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology.

Abstract 203: Differences Between Mammalian and Drosophila Mitochondrial Calcium Handling Help Identify Mechanisms Regulating the Permeability Transition.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Dipayan Chaudhuri ◽  
David E Clapham
Keyword(s):  
Mammalian Cells ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Species ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Calcium Handling ◽  
Mitochondrial Depolarization ◽  
Mitochondrial Permeability

Studies of cardiomyocyte death during calcium overload induced by ischemia-reperfusion injury or heart failure have implicated the mitochondrial permeability transition as a key pathway. During the permeability transition, an opening of a channel in the inner membrane leads to mitochondrial depolarization and swelling. Despite extensive studies in mammalian systems, the machinery responsible for this phenomenon remains only partially identified. If present in non-mammalian species, the components of the permeability transition may be further elucidated, given potential advantages within these systems for high-throughput screens. However, the existence of a permeability transition remains controversial in non-mammalian organisms. In Drosophila , prior studies have documented calcium-induced mitochondrial depolarization, but no obvious swelling. Here we show that Drosophila S2R+ cells do possess the machinery for permeability transition, but that the threshold for a calcium trigger is significantly higher than in mammalian systems. Using a calcein-loading method, we show that Drosophila permeability transition can be triggered by calcium overload, using ionomycin, and by cysteine oxidation, using phenylarsine oxide. As in mammalian systems, blockade of mitochondrial cyclophilin or the ATP/ADP transporter appears to inhibit the Drosophila permeability transition. Finally, we examine three alternative hypotheses that may explain these differences in permeability transition. First, we test if perturbing the pathways for calcium influx into S2R+ mitochondria can trigger this phenomenon. Second, we test if the discrepancy in the calcium threshold is due to structural differences in the key regulators, particularly the mitochondrial cyclophilin. Third, we compare Drosophila and human genomes to see if any novel molecules may be responsible for setting the lower threshold for calcium-induced permeability transition in mammalian cells. Since the Drosophila cells possess such significant resistance to permeability transition, the results of our investigations suggest potential new strategies for the development of therapeutics inhibiting mitochondrial permeability transition in cardiac calcium-induced injury.

Mitochondrial calcium exchange in physiology and disease

2021 ◽  
Author(s):  
Joanne F Garbincius ◽  
John W. Elrod
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuromuscular Disorders ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Genetic Identification ◽  
Calcium Flux ◽  
Great Promise ◽  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Fundamental Biological Process

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.

scholarly journals Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wenchang Zhou ◽  
Fabrizio Marinelli ◽  
Corrine Nief ◽  
José D Faraldo-Gómez
Keyword(s):  
Atp Synthase ◽  
Mitochondrial Permeability Transition Pore ◽  
Catalytic Domain ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Ion Conductance ◽  
Mitochondrial Permeability ◽  
C Subunit

Pathological metabolic conditions such as ischemia induce the rupture of the mitochondrial envelope and the release of pro-apoptotic proteins, leading to cell death. At the onset of this process, the inner mitochondrial membrane becomes depolarized and permeable to osmolytes, proposedly due to the opening of a non-selective protein channel of unknown molecular identity. A recent study purports that this channel, referred to as Mitochondrial Permeability Transition Pore (MPTP), is formed within the c-subunit ring of the ATP synthase, upon its dissociation from the catalytic domain of the enzyme. Here, we examine this claim for two c-rings of different lumen width, through calculations of their ion conductance and selectivity based on all-atom molecular dynamics simulations. We also quantify the likelihood that the lumen of these c-rings is in a hydrated, potentially conducting state rather than empty or blocked by lipid molecules. These calculations demonstrate that the structure and biophysical properties of a correctly assembled c-ring are inconsistent with those attributed to the MPTP.

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