|Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. |
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; Bayır, H; Kagan, VE
Nature cell biology
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.
|Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3). |
Wiedmer, T; Zhao, J; Li, L; Zhou, Q; Hevener, A; Olefsky, JM; Curtiss, LK; Sims, PJ
Proceedings of the National Academy of Sciences of the United States of America
The phospholipid scramblases (PLSCR1 to PLSCR4) are a structurally and functionally unique class of proteins, which are products of a tetrad of genes conserved from Caenorhabditis elegans to humans. The best characterized member of this family, PLSCR1, is implicated in the remodeling of the transbilayer distribution of plasma membrane phospholipids but is also required for normal signaling through select growth factor receptors. Mice with targeted deletion of PLSCR1 display perinatal granulocytopenia due to defective response of hematopoietic precursors to granulocyte colony-stimulating factor and stem cell factor. To gain insight into the biologic function of another member of the PLSCR family, we investigated mice with targeted deletion of PLSCR3, a protein that like PLSCR1 is expressed in many blood cells but which, by contrast to PLSCR1, is also highly expressed in fat and muscle. PLSCR3(-/-) mice at 2 months of age displayed aberrant accumulation of abdominal fat when maintained on standard rodent chow, which was accompanied by insulin resistance, glucose intolerance, and dyslipidemia. Primary adipocytes and cultured bone-marrow-derived macrophages from PLSCR3(-/-) mice were engorged with neutral lipid, and adipocytes displayed defective responses to exogenous insulin. Plasma of PLSCR3(-/-) mice was elevated in non-high-density lipoproteins, cholesterol, triglycerides, nonesterified fatty acids, and leptin, whereas adiponectin was low. These data suggest that the expression of PLSCR3 may be required for normal adipocyte and/or macrophage maturation or function and raise the possibility that deletions or mutations affecting the PLSCR3(-/-) gene locus may contribute to the risk for lipid-related disorders in humans.