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A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis

Abstract

Fusion of vesicles into target membranes during many types of regulated exocytosis requires both SNARE-complex proteins and fusogenic lipids, such as phosphatidic acid. Mitochondrial fusion is less well understood but distinct, as it is mediated instead by the protein Mitofusin (Mfn). Here, we identify an ancestral member of the phospholipase D (PLD) superfamily of lipid-modifying enzymes that is required for mitochondrial fusion. Mitochondrial PLD (MitoPLD) targets to the external face of mitochondria and promotes trans-mitochondrial membrane adherence in a Mfn-dependent manner by hydrolysing cardiolipin to generate phosphatidic acid. These findings reveal that although mitochondrial fusion and regulated exocytic fusion are mediated by distinct sets of protein machinery, the underlying processes are unexpectedly linked by the generation of a common fusogenic lipid. Moreover, our findings suggest a novel basis for the mitochondrial fragmentation observed during apoptosis.

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Figure 1: Dimerized MitoPLD localizes to the mitochondrial exterior.
Figure 2: MitoPLD aggregates mitochondria.
Figure 3: MitoPLD is required for fusion.
Figure 4: MitoPLD functions downstream of Mfn.
Figure 5: MitoPLD hydrolyses cardiolipin to generate phosphatidic acid.

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Acknowledgements

We thank U. Moll, C. Kisker, J. C. Hsieh, G. Rodomen, S. Van Horn, M. Fuller, M. Rojo, R. J. Youle, D. Bogenhagen, J. Vicogne, A. Neiman, G. Du, S. Tsirka and members of the Frohman lab for technical advice and assistance, reagents and critical discussions. The work was supported by awards National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; 64166) and National Institute of General Medical Sciences (NIGMS; 71520) to M.A.F., a National Research Service Award (NRSA) T32 fellowship to G.M.J., and a fellowship award to S.Y.C. from the United Mitochondrial Disease Foundation.

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S.Y.C. and M.A.F. conceived the project. S.Y.C. performed most of the experiments with additional contributions from P.H., G.M.J. and J.S. D.C. provided Mfn-deficient cell lines and technical advice. The manuscript was mostly written by S.Y.C. and M.A.F.

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Correspondence to Michael A. Frohman.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3 and Supplementary Methods (PDF 1736 kb)

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Choi, SY., Huang, P., Jenkins, G. et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 8, 1255–1262 (2006). https://doi.org/10.1038/ncb1487

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