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Biochemistry (Moscow)

, Volume 83, Issue 10, pp 1263–1278 | Cite as

Does Oxidation of Mitochondrial Cardiolipin Trigger a Chain of Antiapoptotic Reactions?

  • A. Y. MulkidjanianEmail author
  • D. N. Shalaeva
  • K. G. Lyamzaev
  • B. V. Chernyak
Hypothesis

Abstract

Oxidative stress causes selective oxidation of cardiolipin (CL), a fourtail lipid specific for the inner mitochondrial membrane. Interaction with oxidized CL transforms cytochrome c into peroxidase capable of oxidizing even more CL molecules. Ultimately, this chain of events leads to the pore formation in the outer mitochondrial membrane and release of mitochondrial proteins, including cytochrome c, into the cytoplasm. In the cytoplasm, cytochrome c promotes apoptosome assembly that triggers apoptosis (programmed cell death). Because of this amplification cascade, even an occasional oxidation of a single CL molecule by endogenously formed reactive oxygen species (ROS) might cause cell death, unless the same CL oxidation triggers a separate chain of antiapoptotic reactions that would prevent the CL-mediated apoptotic cascade. Here, we argue that the key function of CL in mitochondria and other coupling membranes is to prevent proton leak along the interface of interacting membrane proteins. Therefore, CL oxidation should increase proton permeability through the CL-rich clusters of membrane proteins (CL islands) and cause a drop in the mitochondrial membrane potential (MMP). On one hand, the MMP drop should hinder ROS generation and further CL oxidation in the entire mitochondrion. On the other hand, it is known to cause rapid fission of the mitochondrial network and formation of many small mitochondria, only some of which would contain oxidized CL islands. The fission of mitochondrial network would hinder apoptosome formation by preventing cytochrome c release from healthy mitochondria, so that slowly working protein quality control mechanisms would have enough time to eliminate mitochondria with the oxidized CL. Because of these two oppositely directed regulatory pathways, both triggered by CL oxidation, the fate of the cell appears to be determined by the balance between the CL-mediated proapoptotic and antiapoptotic reactions. Since this balance depends on the extent of CL oxidation, mito-chondria-targeted antioxidants might be able to ensure cell survival in many pathologies by preventing CL oxidation.

Keywords

reactive oxygen species mitochondria-targeted antioxidants lipid peroxidation proton leak membrane potential mitophagy 

Abbreviations

CL

cardiolipin

CLOO

cardiolipin peroxide radical

IMM

inner mitochondrial membrane

MAC

mitochondrial anion carrier

MMP

mitochondrial membrane potential

OMM

outer mitochondrial membrane

OMP

outermembrane pore

ROS

reactive oxygen species

UCP

uncoupling protein

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Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • A. Y. Mulkidjanian
    • 1
    • 2
    • 3
    Email author
  • D. N. Shalaeva
    • 1
  • K. G. Lyamzaev
    • 1
  • B. V. Chernyak
    • 1
  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  2. 2.School of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
  3. 3.Department of PhysicsOsnabrueck UniversityOsnabrueckGermany

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