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

Chu, Charleen T.; Ji, Jing; Dagda, Ruben K.; Jiang, Jian Fei; Tyurina, Yulia Y.; Kapralov, Alexandr A.; Tyurin, Vladimir A.; Yanamala, Naveena; Shrivastava, Indira H.; Mohammadyani, Dariush; Wang, Kent Zhi Qiang; Zhu, Jianhui; Klein-Seetharaman, Judith; Balasubramanian, Krishnakumar; Amoscato, Andrew A.; Borisenko, Grigory; Huang, Zhentai; Gusdon, Aaron M.; Cheikhi, Amin; Steer, Erin K.; Wang, Ruth; Baty, Catherine; Watkins, Simon; Bahar, Ivet; Bayir, Hülya; Kagan, Valerian E.

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

Published Date:

Sep 15 2013

Source:

Nat Cell Biol. 15(10):1197-1205.

[PDF-1.14 MB]

Details:

Alternative Title:

Nat Cell Biol

Personal Author:

Chu, Charleen T. ; Ji, Jing ; Dagda, Ruben K. ; Jiang, Jian Fei ; Tyurina, Yulia Y. ; ... More ▼

Description:

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.

Subject:

[+]

Pubmed ID:

24036476

Pubmed Central ID:

PMC3806088

Document Type:

Journal Article

Funding:

AG026389/AG/NIA NIH HHS/United States ; ES020693/ES/NIEHS NIH HHS/United States ; F32 AG030821/AG/NIA NIH HHS/United States ; F32AG030821/AG/NIA NIH HHS/United States ; HL70755/HL/NHLBI NIH HHS/United States ; ... More ▼

Collection(s):

CDC Public Access

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