Loss of Molecular Interaction between Cytochrome c and Cardiolipin Due to Lipid Peroxidation

Shidoji, Yoshihiro; Hayashi, Katsuhiro; Komura, Sadaaki; Ohishi, Nobuko; Yagi, Kunio

doi:10.1006/bbrc.1999.1410

Cited by 228 publications

(157 citation statements)

References 25 publications

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“…3) [67,68]. This is consistent with recent findings showing that in CL-deficient cells, a greater fraction of cytochrome c is free or loosely bound [52].…”

Section: Cardiolipin In Relation To Apoptosissupporting

confidence: 91%

Cardiolipin: Setting the beat of apoptosis

2007

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Cardiolipin (CL) is a mitochondria-specific phospholipid which is known to be intimately linked with the mitochondrial bioenergetic machinery. Accumulating evidence now suggests that this unique lipid also has active roles in several of the mitochondria-dependant steps of apoptosis. CL is closely associated with cytochrome c at the outer leaflet of the mitochondrial inner membrane. This interaction makes the process of cytochrome c release from mitochondria more complex than previously assumed, requiring more than pore formation in the mitochondrial outer membrane. While CL peroxidation could be crucial for enabling cytochrome c dissociation from the mitochondrial inner membrane, cytochrome c itself catalyzes CL peroxidation. Moreover, peroxy-CL directly activates the release of cytochrome c and other apoptogenic factors from the mitochondria. CL is also directly involved in mitochondrial outer membrane permeabilization by enabling docking and activation of proapoptotic Bcl-2 proteins. It appears therefore that CL has multiple roles in apoptosis and that CL metabolism contributes to the complexity of the apoptotic process.

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“…3) [67,68]. This is consistent with recent findings showing that in CL-deficient cells, a greater fraction of cytochrome c is free or loosely bound [52].…”

Section: Cardiolipin In Relation To Apoptosissupporting

confidence: 91%

Cardiolipin: Setting the beat of apoptosis

2007

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“…PerkinElmer Life Sciences supplied the [4][5][6][7][8][9][10][11][12][13][14] C]Ch, glycerol tri- [9,10-3 H]oleate, and 1-palmitoyl-2-[1-…”

Section: Methodsmentioning

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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“…Cytochrome c is normally bound to cardiolipin on the inner mitochondrial membrane, but peroxidation causes the release of cytochrome c (74). Addition of peroxynitrite to isolated mitochondria causes lipid peroxidation and thiol cross-linking associated with increased proton and ion permeability, depolarisation and rapid swelling, which in the absence of calcium are not mediated by MPT (29).…”

Section: No-induced Cell Deathmentioning

confidence: 99%