Sci. Signal., 26 July 2011
Cell Biology MIEF1 as Fission Relief
Annalisa M. VanHook
Science Signaling, AAAS, Washington, DC 20005, USA
The balance between fission and fusion events controls both the form and function of mitochondria and is regulated by various environmental and internal stimuli, such as cellular energy status. Molecular components required at the mitochondrial outer membrane for fission include the dynamin-like guanosine triphosphatase (GTPase) Drp1; mitochondrial fission factor (Mff), which is required for recruitment of Drp1 to the outer membrane; and the integral membrane protein hFis1, which has been implicated as the receptor for Drp1. Mitofusins 1 and 2 (Mfn1 and Mfn2) are fusion-promoting dynamin-like GTPases that are also localized to the outer membrane. Zhao et al. have identified an additional component of the machinery that regulates mitochondrial dynamics. MIEF1 (mitochondrial elongation factor 1) was identified from a database of green fluorescent protein (GFP)–tagged fusion proteins and induced mitochondrial elongation when ectopically expressed in human 293T cells. Conversely, depletion of MIEF1 by RNA interference led to mitochondrial fragmentation. MIEF1 was present on mitochondrial membranes in puncta and at sites of contact between adjacent mitochondria. Based on mitochondrial morphology, overexpression of MIEF1 promoted mitochondrial fusion in a manner distinct from that of Mfn2 overexpression. MIEF1 colocalized with Drp1 on mitochondria, and the two proteins coimmunoprecipitated from cell lysates. Overexpressed MIEF1 recruited cytoplasmic Drp1 to the mitochondrial outer membrane, and deletion of MIEF1s transmembrane domain prevented its colocalization with Drp1 and caused a mitochondrial elongation phenotype similar to that of dominant-negative Drp1 mutants. Binding to MIEF1 decreased the GTPase activity of Drp1, implying that MIEF1 promoted fusion by interfering with Drp1s fission-inducing activity. Mfn2, hFis1, and Mfn2 were not required for MIEF1 to recruit Drp1 to the membrane, but MIEF1 did coimmunoprecipitate with hFis1 and colocalize with hFis1 independent of MIEF1s ability to bind to Drp1. Similarly, the interaction of Drp1 with MIEF1 was independent of hFis1. Overexpression of hFis1 decreased MIEF1-induced mitochondrial fusion, suggesting that MIEF1 may affect fusion by a Drp1-independent mechanism or that the inhibition of Drp1 may be overcome by enhancing recruitment though hFis1. The authors propose a model in which MIEF1 sequesters Drp1, thus preventing it from interacting with hFis1 to promote fission. MIEF1 has no homologs in yeast or invertebrates, highlighting the fact that the mechanisms that regulate mitochondrial dynamics differ between yeast and vertebrates.
J. Zhao, T. Liu, S. Jin, X. Wang, M. Qu, P. Uhlén, N. Tomilin, O. Shupliakov, U. Lendahl, M. Nistér, Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission. EMBO J. 30, 2762–2778 (2011). [PubMed]
Citation: A. M. VanHook, MIEF1 as Fission Relief. Sci. Signal. 4, ec211 (2011).
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