Mechanism of respiration-driven proton translocation in the inner mitochondrial membrane. Kinetics of proton translocation and role of cations

The diverse functions of retinal amacrine cells are reliant on the physiological properties of their synapses. Here we examine the role of mitochondria as Ca2+ buffering organelles in synaptic transmission between GABAergic amacrine cells. We used the protonophore p-trifluoromethoxy-phenylhydrazone (FCCP) to dissipate the membrane potential across the inner mitochondrial membrane that normally sustains the activity of the mitochondrial Ca2+ uniporter. Measurements of cytosolic Ca2+ levels reveal that prolonged depolarization-induced Ca2+ elevations measured at the cell body are altered by inhibition of mitochondrial Ca2+ uptake. Furthermore, an analysis of the ratio of Ca2+ efflux on the plasma membrane Na-Ca exchanger to influx through Ca2+ channels during voltage steps indicates that mitochondria can also buffer Ca2+ loads induced by relatively brief stimuli. Importantly, we also demonstrate that mitochondrial Ca2+ uptake operates at rest to help maintain low cytosolic Ca2+ levels. This aspect of mitochondrial Ca2+ buffering suggests that in amacrine cells, the normal function of Ca2+-dependent mechanisms would be contingent upon ongoing mitochondrial Ca2+ uptake. To test the role of mitochondrial Ca2+ buffering at amacrine cell synapses, we record from amacrine cells receiving GABAergic synaptic input. The Ca2+ elevations produced by inhibition of mitochondrial Ca2+uptake are localized and sufficient in magnitude to stimulate exocytosis, indicating that mitochondria help to maintain low levels of exocytosis at rest. However, we found that inhibition of mitochondrial Ca2+ uptake during evoked synaptic transmission results in a reduction in the charge transferred at the synapse. Recordings from isolated amacrine cells reveal that this is most likely due to the increase in the inactivation of presynaptic Ca2+ channels observed in the absence of mitochondrial Ca2+ buffering. These results demonstrate that mitochondrial Ca2+ buffering plays a critical role in the function of amacrine cell synapses.

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The role of nitric oxide signaling in food intake; insights from the inner mitochondrial membrane peptidase 2 mutant mice

Redox Biology ◽

10.1016/j.redox.2013.10.003 ◽

2013 ◽

Vol 1 (1) ◽

pp. 498-507 ◽

Cited By ~ 15

Author(s):

Changjie Han ◽

Qingguo Zhao ◽

Baisong Lu

Keyword(s):

Nitric Oxide ◽

Food Intake ◽

Mitochondrial Membrane ◽

Mutant Mice ◽

Inner Mitochondrial Membrane ◽

Nitric Oxide Signaling

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Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants

Quarterly Reviews of Biophysics ◽

10.1017/s0033583500005795 ◽

1996 ◽

Vol 29 (2) ◽

pp. 169-202 ◽

Cited By ~ 478

Author(s):

Vladimir P. Skulachev

Keyword(s):

Resting State ◽

Mitochondrial Membrane ◽

High Rate ◽

Oxygen Species ◽

Inner Mitochondrial Membrane ◽

Enzymatic Formation ◽

Male Sex ◽

Low Levels ◽

Cellular Components

AbstractTo proceed at a high rate, phosphorylating respiration requires ADP to be available. In the resting state, when the energy consumption is low, the ADP concentration decreases so that phosphorylating respiration ceases. This may result in an increase in the intracellular concentrations of O2as well as of one-electron O2reductants such asThese two events should dramatically enhance non-enzymatic formation of reactive oxygen species, i.e. of, and OHׁ, and, hence, the probability of oxidative damage to cellular components. In this paper, a concept is put forward proposing that non-phosphorylating (uncoupled or non-coupled) respiration takes part in maintenance of low levels of both O2and the O2reductants when phosphorylating respiration fails to do this job due to lack of ADP.In particular, it is proposed that some increase in the H+leak of mitochondrial membrane in State 4 lowers, stimulates O2consumption and decreases the level ofwhich otherwise accumulates and serves as one-electron O2reductant. In this connection, the role of natural uncouplers (thyroid hormones), recouplers (male sex hormones and progesterone), non-specific pore in the inner mitochondrial membrane, and apoptosis, as well as of non-coupled electron transfer chains in plants and bacteria will be considered.

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Cytoprotective Role of Ca2+- Activated K+ Channels in the Cardiac Inner Mitochondrial Membrane

Science ◽

10.1126/science.1074360 ◽

2002 ◽

Vol 298 (5595) ◽

pp. 1029-1033 ◽

Cited By ~ 348

Author(s):

W. Xu ◽

Y. Liu ◽

S. Wang ◽

T. McDonald ◽

J. E. Van Eyk ◽

...

Keyword(s):

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane ◽

K Channels

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Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.765973 ◽

2021 ◽

Vol 9 ◽

Author(s):

Pooja Patel ◽

Arielys Mendoza ◽

Dexter J. Robichaux ◽

Meng C. Wang ◽

Xander H. T. Wehrens ◽

...

Keyword(s):

Cell Death ◽

Mitochondrial Dysfunction ◽

Family Member ◽

Mitochondrial Membrane ◽

Mitochondrial Permeability Transition ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Inner Mitochondrial Membrane ◽

Retention Capacity

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.

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Role of cytochrome c heme lyase in mitochondrial import and accumulation of cytochrome c in Saccharomyces cerevisiae.

Molecular and Cellular Biology ◽

10.1128/mcb.11.11.5487 ◽

1991 ◽

Vol 11 (11) ◽

pp. 5487-5496 ◽

Cited By ~ 105

Author(s):

M E Dumont ◽

T S Cardillo ◽

M K Hayes ◽

F Sherman

Keyword(s):

Saccharomyces Cerevisiae ◽

Cytochrome C ◽

Mitochondrial Membrane ◽

Intermembrane Space ◽

Inner Mitochondrial Membrane ◽

Yeast Saccharomyces Cerevisiae ◽

Apocytochrome C ◽

Cytochrome C Heme Lyase

Heme is covalently attached to cytochrome c by the enzyme cytochrome c heme lyase. To test whether heme attachment is required for import of cytochrome c into mitochondria in vivo, antibodies to cytochrome c have been used to assay the distributions of apo- and holocytochromes c in the cytoplasm and mitochondria from various strains of the yeast Saccharomyces cerevisiae. Strains lacking heme lyase accumulate apocytochrome c in the cytoplasm. Similar cytoplasmic accumulation is observed for an altered apocytochrome c in which serine residues were substituted for the two cysteine residues that normally serve as sites of heme attachment, even in the presence of normal levels of heme lyase. However, detectable amounts of this altered apocytochrome c are also found inside mitochondria. The level of internalized altered apocytochrome c is decreased in a strain that completely lacks heme lyase and is greatly increased in a strain that overexpresses heme lyase. Antibodies recognizing heme lyase were used to demonstrate that the enzyme is found on the outer surface of the inner mitochondrial membrane and is not enriched at sites of contact between the inner and outer mitochondrial membranes. These results suggest that apocytochrome c is transported across the outer mitochondrial membrane by a freely reversible process, binds to heme lyase in the intermembrane space, and is then trapped inside mitochondria by an irreversible conversion to holocytochrome c accompanied by folding to the native conformation. Altered apocytochrome c lacking the ability to have heme covalently attached accumulates in mitochondria only to the extent that it remains bound to heme lyase.

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Role of Cardiolipins in the Inner Mitochondrial Membrane: Insight Gained through Atom-Scale Simulations

The Journal of Physical Chemistry B ◽

10.1021/jp8077369 ◽

2009 ◽

Vol 113 (11) ◽

pp. 3413-3422 ◽

Cited By ~ 47

Author(s):

Tomasz Róg ◽

Hector Martinez-Seara ◽

Nana Munck ◽

Matej Orešič ◽

Mikko Karttunen ◽

...

Keyword(s):

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane

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Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

Cells ◽

10.3390/cells10071721 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1721

Author(s):

Edward S. Gasanoff ◽

Lev S. Yaguzhinsky ◽

Győző Garab

Keyword(s):

Electron Transport Chain ◽

Mitochondrial Membrane ◽

Mitochondrial Bioenergetics ◽

Mitochondrial Membranes ◽

Inner Mitochondrial Membrane ◽

Atp Production ◽

Functional Roles ◽

Transport Chain ◽

Energy Converting

The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto–Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.

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A possible role of "steroidogenic factor" in the corticoidogenic response to ACTH; Effect of ACTH, cycloheximide and aminoglutethimide on the content of cholesterol in the outer and inner mitochondrial membrane of rat adrenal cortex.

Endocrinologia Japonica ◽

10.1507/endocrj1954.30.335 ◽

1983 ◽

Vol 30 (3) ◽

pp. 335-338 ◽

Cited By ~ 41

Author(s):

YUJI OHNO ◽

KAZUTOSHI YANAGIBASHI ◽

YOSHIKO YONEZAWA ◽

SEIICHI ISHIWATARI ◽

MICHIO MATSUBA

Keyword(s):

Adrenal Cortex ◽

Mitochondrial Membrane ◽

Inner Mitochondrial Membrane

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Snapshot of an oxygen intermediate in the catalytic reaction of cytochrome c oxidase

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814526116 ◽

2019 ◽

Vol 116 (9) ◽

pp. 3572-3577 ◽

Cited By ~ 24

Author(s):

Izumi Ishigami ◽

Ariel Lewis-Ballester ◽

Austin Echelmeier ◽

Gerrit Brehm ◽

Nadia A. Zatsepin ◽

...

Keyword(s):

Protein Conformation ◽

Mitochondrial Membrane ◽

Proton Translocation ◽

Conformational State ◽

Inner Mitochondrial Membrane ◽

Time Resolved ◽

Metal Centers ◽

Redox States ◽

Distinct Structure ◽

Serial Femtosecond Crystallography

Cytochrome c oxidase (CcO) reduces dioxygen to water and harnesses the chemical energy to drive proton translocation across the inner mitochondrial membrane by an unresolved mechanism. By using time-resolved serial femtosecond crystallography, we identified a key oxygen intermediate of bovine CcO. It is assigned to the PR-intermediate, which is characterized by specific redox states of the metal centers and a distinct protein conformation. The heme a3 iron atom is in a ferryl (Fe4+ = O2−) configuration, and heme a and CuB are oxidized while CuA is reduced. A Helix-X segment is poised in an open conformational state; the heme a farnesyl sidechain is H-bonded to S382, and loop-I-II adopts a distinct structure. These data offer insights into the mechanism by which the oxygen chemistry is coupled to unidirectional proton translocation.

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