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Nat Cell Biol. 2013 Oct;15(10):1197-1205. doi: 10.1038/ncb2837. Epub 2013 Sep 15.

Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.

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Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213.
Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15213.
Department of Critical Care Medicine and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213.
Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15213.
Department of Computational and Systems Biology, University of Pittsburgh, PA 15213.
Department of Cell Biology and Physiology and Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213.
Contributed equally


Recognition of injured mitochondria for degradation by macroautophagy is essential for cellular health, but the mechanisms remain poorly understood. Cardiolipin is an inner mitochondrial membrane phospholipid. We found that rotenone, staurosporine, 6-hydroxydopamine and other pro-mitophagy stimuli caused externalization of cardiolipin to the mitochondrial surface in primary cortical neurons and SH-SY5Y cells. RNAi knockdown of cardiolipin synthase or of phospholipid scramblase-3, which transports cardiolipin to the outer mitochondrial membrane, decreased the delivery of mitochondria to autophagosomes. Furthermore, we found that the autophagy protein microtubule-associated-protein-1 light chain 3 (LC3), which mediates both autophagosome formation and cargo recognition, contains cardiolipin-binding sites important for the engulfment of mitochondria by the autophagic system. Mutation of LC3 residues predicted as cardiolipin-interaction sites by computational modelling inhibited its participation in mitophagy. These data indicate that redistribution of cardiolipin serves as an 'eat-me' signal for the elimination of damaged mitochondria from neuronal cells.

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