![]() However, increasing evidence suggests that mammalian Fis1 is not essential for Drp1 recruitment, and overexpression or knockdown of Fis1 does not affect the distribution of Drp1 on mitochondria. In yeast, Fis1p is the major receptor for recruiting Dnm1p (the Drp1 ortholog in yeast) to mitochondria via one of the adaptor proteins Mdv1p and Caf4p. In mammalian cells, four MOM-anchored proteins, i.e., mitochondrial fission factor (Mff), mitochondrial elongation factor 1 and 2 (MIEF1 and MIEF2, also known as MiD51 and MiD49), and mitochondrial fission 1 (Fis1), are currently known to serve as receptors for recruiting Drp1 to mitochondria. The mode of Drp1 recruitment appears to differ between mammals and yeast. However, unlike Mfns and OPA1, Drp1 does not contain any membrane-anchored domains, and recruitment of Drp1 to mitochondria therefore represents a crucial step in regulating Drp1-mediated mitochondrial division. Drp1 can be recruited from the cytosol to the mitochondrial surface, where it is assembled into higher-oligomeric ring complexes to wrap around the mitochondria, mediating mitochondrial division via its GTPase activity. Drp1 plays a central role in the mitochondrial division, and it is a dynamin-related GTPase predominantly residing in the cytosol. On the fission side, dynamin-related protein 1 (Drp1) together with Mff, MIEFs (MIEF1 and MIEF2), and Fis1 constitute the core components of the mammalian fission machinery. Mfn1 and Mfn2 are responsible for the fusion of the outer mitochondrial membranes, whereas OPA1 is responsible for the fusion of the inner membranes. In mammalian cells, the mitochondrial fusion machinery contains three key components, including two mitochondrial outer membrane (MOM)-anchored dynamin-related GTPases, mitofusin 1 and 2 (Mfn1 and Mfn2), and one mitochondrial inner membrane (MIM)-anchored GTPase, optic atrophy 1 (OPA1). Mitochondria-shaping proteins are generally classified as participating either in the mitochondrial fission or fusion machinery. The dynamic changes in morphology, referred to as mitochondrial dynamics, are controlled by a set of mitochondria-shaping proteins through fission- and fusion-promoting programs, which counterbalance each other. Consequently, mitochondrial morphology is highly variable and takes on different shapes, such as small spheres, short tubules, and long tubular networks. Mitochondria frequently change their morphology, size, and distribution via fission and fusion events to respond to altered metabolic demands or pathogenic assaults to the cell. Our study suggests that MIEFs serve as a central hub that interacts with and regulates both the fission and fusion machineries, which uncovers a novel mechanism for balancing these opposing forces of mitochondrial dynamics in mammals. In addition, we show that MIEF1/2 can competitively decrease the interaction of hFis1 with Mfn1 and Mfn2, alleviating hFis1-induced mitochondrial fragmentation and contributing to mitochondrial fusion. Moreover, mitochondrial localization and self-association of MIEFs are crucial for their fusion-promoting ability. Elevated levels of MIEFs enhance mitochondrial fusion in an Mfn1/2- and OPA1-dependent but Drp1-independent manner. We show that MIEFs (MIEF1/2), besides their action in the fission machinery, regulate mitochondrial fusion through direct interaction with the fusion proteins Mfn1 and Mfn2, suggesting that MIEFs participate in not only fission but also fusion. In the present work, we analyzed the roles of mitochondrial elongation factors 1 and 2 (MIEF1/2), core components of the fission machinery in mammals. These proteins are generally considered to be binary components of either the fission or fusion machinery, but potential crosstalk between the fission and fusion machineries remains less explored. Mitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins. ![]()
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