Topology of the Mitochondrial Inner Membrane: Dynamics and Bioenergetic Implications

Mannella, Carmen A.; Pfeiffer, Douglas R.; Bradshaw, Patrick C.; Moraru, Ion I.; Slepchenko, Boris M.; Loew, Leslie M.; Hsieh, Chyongere; Buttle, Karolyn; Marko, Michael

doi:10.1080/15216540152845885

Cited by 220 publications

(181 citation statements)

References 20 publications

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“…Second, substantial tBid binding has been observed at non-contact loci (25), demonstrating that recognizable OM CL is not restricted to contact sites. Third, tomographic examination of mitochondria in a relatively unperturbed state (68,69) has revealed far fewer contact sites than previously estimated by electron microscopy.…”

Section: Discussionmentioning

confidence: 99%

Permeabilization of the Mitochondrial Outer Membrane by Bax/Truncated Bid (tBid) Proteins as Sensitized by Cardiolipin Hydroperoxide Translocation

Korytowski

Basova

Piłat

et al. 2011

Journal of Biological Chemistry

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Cytochrome c (cyt c) release upon oxidation of cardiolipin (CL) in the mitochondrial inner membrane (IM) under oxidative stress occurs early in the intrinsic apoptotic pathway. We postulated that CL oxidation mobilizes not only cyt c but also CL itself in the form of hydroperoxide (CLOOH) species. Relatively hydrophilic CLOOHs could assist in apoptotic signaling by translocating to the outer membrane (OM), thus promoting recruitment of the pro-apoptotic proteins truncated Bid (tBid) and Bax for generation of cyt c-traversable pores. Initial testing of these possibilities showed that CLOOH-containing liposomes were permeabilized more readily by tBid plus Ca 2؉ than CL-containing counterparts. Moreover, CLOOH translocated more rapidly from IM-mimetic to OM-mimetic liposomes than CL and permitted more extensive OM permeabilization. We found that tBid bound more avidly to CLOOH-containing membranes than to CL counterparts, and binding increased with increasing CLOOH content. Permeabilization of CLOOH-containing liposomes in the presence of tBid could be triggered by monomeric Bax, consistent with tBid/Bax cooperation in pore formation. Using CL-null mitochondria from a yeast mutant, we found that tBid binding and cyt c release were dramatically enhanced by transfer acquisition of CLOOH. Additionally, we observed a pre-apoptotic IM-to-OM transfer of oxidized CL in cardiomyocytes treated with the Complex III blocker, antimycin A. These findings provide new mechanistic insights into the role of CL oxidation in the intrinsic pathway of oxidative apoptosis.Cytochrome c (cyt c) 2 dissociation from the mitochondrial inner membrane (IM), movement into the intermembrane space, and then release into cytosol is recognized as a key early event in the intrinsic (mitochondrion-initiated) pathway of oxidative stress-induced apoptosis (1-3). How this occurs is still not completely understood, but accumulating evidence suggests that oxidative modification of cardiolipin (CL), e.g. conversion to hydroperoxide species (CLOOHs), plays an important role (4 -7). CL (diphosphatidylglycerol) is located primarily in the mitochondrial IM of normal eukaryotic cells, where it interacts with and supports the functions of cyt c, Complex III (cytochromes b and c 1 ), and Complex IV (cytochrome c oxidase) (8). Unlike most other phospholipids in which only the sn-2 fatty acyl group is unsaturated, both sn-1 and sn-2 groups of natural CL are typically unsaturated. In mammalian heart, for example, tetra-linoleoyl CL composes 75-80% of overall CL molecular species (9). Consequently, CL oxidizability and -OOH content per average oxidized molecule are typically much higher than for more conventional phospholipids such as those in the phosphatidylcholine and phosphatidylethanolamine families. Model studies with bovine heart CL in thin film or liposomal form have shown that its normally strong interaction with some fraction of IM cyt c is progressively weakened with increasing -OOH content (4), suggesting possible involvement in pro-apoptotic cyt c releas...

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Section: Discussionmentioning

confidence: 99%

Permeabilization of the Mitochondrial Outer Membrane by Bax/Truncated Bid (tBid) Proteins as Sensitized by Cardiolipin Hydroperoxide Translocation

Korytowski

Basova

Piłat

et al. 2011

Journal of Biological Chemistry

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“…The inner mitochondrial membrane is highly folded into cristae (1)(2)(3), which contain the bulk of the respiratory chain complexes and the mitochondrial F 1 F o ATP synthase (4,5). At the cristae ridges, the ATP synthase self-assembles into long rows of dimers, which maintain a high local membrane curvature and normal cristae architecture (1,6,7).…”

mentioning

confidence: 99%

Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria

Daum

Walter

Horst

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

214

195

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Aging is one of the most fundamental, yet least understood biological processes that affect all forms of eukaryotic life. Mitochondria are intimately involved in aging, but the underlying molecular mechanisms are largely unknown. Electron cryotomography of whole mitochondria from the aging model organism Podospora anserina revealed profound age-dependent changes in membrane architecture. With increasing age, the typical cristae disappear and the inner membrane vesiculates. The ATP synthase dimers that form rows at the cristae tips dissociate into monomers in inner-membrane vesicles, and the membrane curvature at the ATP synthase inverts. Dissociation of the ATP synthase dimer may involve the peptidyl prolyl isomerase cyclophilin D. Finally, the outer membrane ruptures near large contact-site complexes, releasing apoptogens into the cytoplasm. Inner-membrane vesiculation and dissociation of ATP synthase dimers would impair the ability of mitochondria to supply the cell with sufficient ATP to maintain essential cellular functions.subtomogram averaging | cell death

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“…Such a change comes about by fission of pre-existing mitochondria; also the reverse, i.e., fusion of mitochondria occurs and is a means for regulation. In addition to these inter-mitochondrial alterations, changes within mitochondria are also observed (Mannella et al, 2001). Mainly fusion and fission of the inner mitochondrial membrane seem to occur, and have been proposed to play a functional role in the organelle; these structural changes may affect diffusion of protons as well as proteins (e.g., cytochrome C).…”

Section: Structural Dynamics and Biogenesis Of Mitochondriamentioning

confidence: 99%

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

Mulder

Ling

2009

Molecular and Cellular Endocrinology

107

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Mitochondrial metabolism controls insulin secretion from the pancreatic β-cell. Type 2 Diabetes evolves when the β-cells fail to release appropriate amounts of insulin, causing metabolic dysregulation and hyperglycemia. It is attractive to assume that mitochondrial dysfunction plays a decisive role in these processes. Indeed, while being a rare condition, genetically determined dysfunction of mitochondria causes a Type 2 Diabetes-like syndrome.Here, we review what is known about mitochondrial dysfunction in the β-cell in Type 2Diabetes. The focus is on observations in humans but relevant studies in animal models of the disease are discussed. A particular emphasis is placed on changes in metabolic enzymes and function in β-cell mitochondria and how altered structure of the organelle appears to facilitate its function. These molecular processes are subject to tight genetic as well as epigenetic control. Variations and implications of these mechanisms are reviewed. The emerging picture is that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in Type 2 Diabetes. Such processes may prove to be targets for therapeutic interventions in the disease.

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Topology of the Mitochondrial Inner Membrane: Dynamics and Bioenergetic Implications

Cited by 220 publications

References 20 publications

Permeabilization of the Mitochondrial Outer Membrane by Bax/Truncated Bid (tBid) Proteins as Sensitized by Cardiolipin Hydroperoxide Translocation

Permeabilization of the Mitochondrial Outer Membrane by Bax/Truncated Bid (tBid) Proteins as Sensitized by Cardiolipin Hydroperoxide Translocation

Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria

Mitochondrial dysfunction in pancreatic β-cells in Type 2 Diabetes

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