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

Authors
Chu-CT; Ji-J; Dagda-RK; Jiang-JF; Tyurina-YY; Kapralov-AA; Tyurin-VA; Yanamala-N; Shrivastava-IH; Mohammadyani-D; Qiang-Wang-KZ; Zhu-J; Klein-Seetharaman-J; Balasubramanian-K; Amoscato-AA; Borisenko-G; Huang-Z; Gusdon-AM; Cheikhi-A; Steer-EK; Wang-R; Baty-C; Watkins-S; Bahar-I; Bayir-H; Kagan-VE.
Source
Nat Cell Biol 2013 Oct; 15(10):1197-1205
NIOSHTIC No.
20043371
Abstract
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.
Keywords
Cell-biology; Cell-function; Cellular-function; Proteins; Biological-function; Biological-effects; Biomechanics
Contact
Charleen T. Chu, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Publication Date
20131001
Document Type
Journal Article
Email Address
ctc4@pitt.edu
Funding Type
Grant
Fiscal Year
2014
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282; M112013
Issue of Publication
10
ISSN
1465-7392
Source Name
Nature Cell Biology
State
PA; NV
Performing Organization
University of Pittsburgh at Pittsburgh
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