TY - JOUR
T1 - Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells
AU - Chu, Charleen T.
AU - Ji, Jing
AU - Dagda, Ruben K.
AU - Jiang, Jian Fei
AU - Tyurina, Yulia Y.
AU - Kapralov, Alexandr A.
AU - Tyurin, Vladimir A.
AU - Yanamala, Naveena
AU - Shrivastava, Indira H.
AU - Mohammadyani, Dariush
AU - Qiang Wang, Kent Zhi
AU - Zhu, Jianhui
AU - Klein-Seetharaman, Judith
AU - Balasubramanian, Krishnakumar
AU - Amoscato, Andrew A.
AU - Borisenko, Grigory
AU - Huang, Zhentai
AU - Gusdon, Aaron M.
AU - Cheikhi, Amin
AU - Steer, Erin K.
AU - Wang, Ruth
AU - Baty, Catherine
AU - Watkins, Simon
AU - Bahar, Ivet
AU - Bayir, Hülya
AU - Kagan, Valerian E.
N1 - Funding Information:
The molecular simulations were supported in part by the National Institutes of Health (P41GM103712 (I.B.) and U19AIO68021 (H.B./V.E.K./I.B.)).
Funding Information:
This study was supported in part by the National Institutes of Health (AG026389 (C.T.C.), NS065789 (C.T.C.), F32AG030821 (R.K.D.), NS061817 (H.B.), HL70755 (V.E.K.), OH008282 (V.E.K.), U19AIO68021 (H.B., V.E.K.), NS076511 (H.B., V.E.K.), ES020693 (V.E.K., Y.Y.T.)). We thank many generous scientists listed in the Methods for gifts of reagents, and D. E. Winnica for assistance with primary neuron cultures.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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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U2 - 10.1038/ncb2837
DO - 10.1038/ncb2837
M3 - Article
C2 - 24036476
AN - SCOPUS:84885176082
SN - 1465-7392
VL - 15
SP - 1197
EP - 1205
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 10
ER -