Cardiolipin at the crossroad between apoptosis and autophagy

Orateur : Patrice X. PETIT (Research Director CNRS CNRS FR3636, Team "mitochondria, apoptosis and autophagy" Institut de Neurosciences, Université Paris-Descartes)

Very recently a wealth of knowledge has accumulated on the role of cardiolipin (CL), the main phospholipid of mitochondria, on the structural orga nization of the inner mitochondrial membrane and many aspects of mitochondrial bioenergetics. The emerging huge interest in this anionic double-charged tetra-acylated lipid found in mitochondria is certainly related to its newly discovered signaling functions. Within the possible manipulations of cellular CL content and quality are the decrease of CL synthesis, possible changes in CL amount and acyl chain composition, the induction of CL oxidation, but also the addition of CL to cells and/or isolated mitochondria. Clearly, addition of CLs leads to curious results, since added CLs act as detergents that perturb both mitochondrial structures and functions. CL synthase (CLS) KO leads to a decrease of CLs without a change in quality and curiously leads to enhanced apoptosis and a shift towards necrosis. Oxidation of CL’s polyunsaturated acyl chains - catalyzed by CL complexes with cytochrome c - is a pro-apoptotic signal, whereas changes in the saturation of the acyl chains towards more unsaturated acyl chains lead to abnormal CLs, inhibition of apoptosis [1] and also inhibition of pro-autophagy signals [2] (i.e., Barth syndrome). Usually, a collapse of the membrane asymmetry represents a pro-mitophageal mechanism whereby externalized CL acts as an “eat-me” signal. Very recently, the messaging functions of myriads of CL species and their oxidation products are now being recognized as important intracellular and extracellular signals for innate and adaptive immune systems [3]. Mutations in the gene that encodes the monolyso-transacylase, TAZ, lead to Barth syndrome. Individuals affected by this X-linked multi-system disorder present with cardiomyopathy, skeletal muscle weakness, neutropenia, growth retardation and methylglutaconic aciduria (3-MGA) and CL abnormalities. Research on various species models or cells derived from Barth syndrome patients provided deep insight into the cellular defects associated with TAZ mutations. Biopsies from the heart, liver and skeletal muscle of patients exhibited malformed and dysfunctional mitochondria. Our recent work has focused on basic aspects of the Barth syndrome, in particular related to CL and tafazzin, providing some clues to better understand the link between Barth syndrome pathology and mitochondrial dysfunction, comprising defects in oxidative phosphorylation and respiratory supercomplex organization, lower ATP production, and slight increase in oxygen radical formation.

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