Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fission

Abstract

Human MIEF1 recruits Drp1 to mitochondrial outer membranes and promotes mitochondrial fusion rather than fissionMitochondrial morphology depends on the balance between fission and fusion events. This study identifies a receptor for the fission factor Drp1 within the mitochondrial outer membrane, which inhibits Drp1-mediated fission and activates fusion.

A Targeted Mutation Identified through pK Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission

“…In sequential models, Mdv1 acts as an obligate adaptor between Fis1 and Dnm1, but no mammalian Mdv1 ortholog has been identified, suggesting that mammalian and yeast fission mechanisms are divergent. This view is supported by a potentially divergent role for Fis1 in mitophagy (9,52,53) and the presence of non-fungal tail anchors (Mff and Mid-49/51) capable of mammalian Dnm1 (Drp1) recruitment independent of Fis1 (13,40,49,51,54,55). However, Fis1 and Dnm1 (Drp1 in mammals) are the only two proteins conserved for mitochondrial fission in all species, and mutating conserved residues in yeast Fis1 disrupts Dnm1 pulldowns, suggesting conserved Fis1/Dnm1 interactions in fission (16).…”

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

“…GTP-binding Assay-The GTP-binding assay was performed according to the previously described procedure, with some modifications (26,27). Briefly, after treatment NCMs were rinsed in ice-cold PBS and collected in GTP-binding buffer (20 mM Tris-HCl pH 7.5, 5 mM MgCl 2 , 2 mM PMSF, 150 mM NaCl, 0.1% Triton X-100, 0.025 mM PUGNAc and 1:1000 diluted protease and phosphase inhibitor mixture (Thermo Scientific)).…”

Mitochondrial Morphology in Metabolic Diseases

“…Additional mitochondrial membrane-bound proteins, mitochondrial dynamics protein 49 and 51 (MiD49 and MiD51)/ mitochondrial elongation factor 1 (MIEF1), were independently identified by two groups (104,158). The proteins MiD49 and 51 were discovered through a screen of uncharacterized human genes for their ability to alter mitochondrial morphology (104), whereas MIEF1 (MiD51) was identified from a screen of a green fluorescent protein (GFP)-tagged library by virtue of its mitochondrial localization (158). MiD49 and MiD51/MIEF1 share 45% homology and a highly conserved N-terminal transmembrane domain that anchors them to the OMM (104,158 (104,158).…”

“…In addition to its function in mitochondrial fusion, cleavage of OPA1 by the presenilin-associated, rhomboid-like (PARL) protease produces a soluble form of OPA1 in the intermembrane space, where it forms a heteromeric complex with the long membrane-bound form at the neck of the cristae to keep the cristae junction closed, preventing cytochrome c release (28,55). (158) and elongated (104) Cyt, cytosol; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane; ER, endoplasmic reticulum; IMS, intermembrane space; OX, overexpression; KD, knockdown; KO, knockout; DLP1, dynamin-like protein 1; Drp1, dynamin-related protein 1; Fis1, fission protein 1; OPA1, optic atrophy 1; MTP18, mitochondrial protein 18 kDa; GDAP1, ganglioside-induced differentiationassociated protein 1; Mff, mitochondrial fission factor; Mfn, mitofusin; MARCH-V, membrane-associated RING-CH-V; MitoPLD, mitochondrial phospholipase D; MIB, Mfn-binding protein; SLP-2, stomatin-like protein 2; MIEF1, mitochondrial elongation factor 1.…”

“…Although it is clear that Mff, hFis1, and DLP1 are bona fide components in mitochondrial fission, further investigation is necessary for defining their functional interactions. Additional mitochondrial membrane-bound proteins, mitochondrial dynamics protein 49 and 51 (MiD49 and MiD51)/ mitochondrial elongation factor 1 (MIEF1), were independently identified by two groups (104,158). The proteins MiD49 and 51 were discovered through a screen of uncharacterized human genes for their ability to alter mitochondrial morphology (104), whereas MIEF1 (MiD51) was identified from a screen of a green fluorescent protein (GFP)-tagged library by virtue of its mitochondrial localization (158).…”