The new roles of cardiolipin in ROS-mediated signalling

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by Alberto Lévano-Martinez

Cardiolipin, the signature phospholipid of mitochondria, has been extensively studied as this organelle’s main structural and regulatory lipid. It exerts influential roles in the catalytic activity of key components of the oxidative phosphorylation under physiological conditions. However, recents advances in mitochondrial physiology have uncovered roles of this phospholipid in pathophysiological situations such as apoptosis, or in Barth syndrome. Cardiolipin anchors cytochrome c to the outer face of the inner mitochondrial membrane, which favors the electron transfer to the terminal component of the respiratory chain (Complex IV). However, during oxidative injury, oxidized acyl chains from cardiolipin promote the release of cytochrome c from its membrane location, therby triggering the apoptotic cascade. Recently, the group of Valerian Kagan in Pittsburgh University uncovered a new role of the oxidation products of cardiolipin as signalling molecules in the early stage of apoptosis. Their discoveries are depicted in Figure 1. Briefly, an oxidative injury from cellular or environmental origin results in the activation of the peroxidase activity of cytochrome c, thus oxidizing the cardiolipin acyl chains (mainly composed of polyinsaturated acyl chains). Ultimately, they are hydrolized by a mitochondrial calcium-dependent phosphalipase A2 and released to the cytoplasm. There, they can exert roles as signaling molecules to activate the antioxidant machinery of the cell and/or to function as pro-inflamatory molecules, similar to tromboxanes and prostaglandins. However, the late and improper activation of such response would trigger the celular death cascade by releasing proapoptotic cytochrome c.

Cytochrome c

Figure 1. A) Cytochrome c (depicted in purple) is anchored to the inner membrane by cardiolipin (depicted in green), where it participates in electron transport. B) An external injury activates the peroxidase activity of cytochrome c, thus oxidizing the polyinsaturaded chains of cardiolipin. C) oxydized acyl chains are hydrolized by phospholipase A2 (in brown). D) Epoxide (in figure) and lipoperoxides are released from mitochondria and exported to cytoplasm.


This article is a comment on a paper by:

Y. Y. Tyurina, S. M. Poloyac, V. A. Tyurin, A. A. Kapralov, J. Jiang, T. S. Anthonymuthu, V. I. Kapralova, A. S. Vikulina, M.-Y. Jung, M. W. Epperly, D. Mohammadyani, J. Klein-Seetharaman, T. C. Jackson, P. M. Kochanek, B. R. Pitt, J. S. Greenberger, Y. A. Vladimirov, H. Bayır,  V. E. Kagan
Mitochondrial pathway for biosynthesis of lipid mediators.
Nature Chemistry, 6: 542-52, 2014. |

Alberto Lévano-Martinez, PhD.,
*The author is a post-doctoral fellow at Alicia Kowaltowski’s laboratory,
Department of Biochemistry, Institute of Chemistry,
University of São Paulo, Brazil

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