MiD49 and MiD51, new components of the mitochondrial fission machinery

Abstract

Mitochondria form intricate networks through fission and fusion events. Here, we identify mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51, respectively) anchored in the mitochondrial outer membrane. MiD49/51 form foci and rings around mitochondria similar to the fission mediator dynaminrelated protein 1 (Drp1). MiD49/51 directly recruit Drp1 to the mitochondrial surface, whereas their knockdown reduces Drp1 association, leading to unopposed fusion. Overexpression of MiD49/51 seems to sequester Drp1 from functioning at mitochondria and cause fused tubules to associate with actin. Thus, MiD49/51 are new mediators of mitochondrial division affecting Drp1 action at mitochondria.

Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage

“…Mitochondrial division is mediated by Drp1, which is mainly located in the cytosol. Drp1 is recruited to the mitochondrial surface by other outer membrane proteins (James et al, 2003;Yoon et al, 2003;Gandre-Babbe and van der Bliek, 2008;Otera et al, 2010;Palmer et al, 2011), where it assembles into spiral structures around mitochondria to induce fission of the mitochondrial membrane (Yoon et al, 2001;Lackner et al, 2009). The importance of mitochondrial dynamics to human health is highlighted by studies showing that mutations in Mfn2 and Opa1 underlie neurological disorders, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, whereas a mutation in Drp1 causes neurodevelopmental abnormalities (Alexander et al, 2000;Delettre et al, 2000;Züchner et al, 2004;Waterham et al, 2007).…”

Mitochondrial Morphology in Metabolic Diseases

“…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).…”

“…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). Counter intuitively, overexpression also resulted in the enhanced mitochondrial association of the fission protein DLP1, which would predict the profission phenotype.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Genetic ablation of Drp1 is embryonically lethal in mice because of abnormal neuronal development [32]. Drp1 does not act alone, but different "accomplices" assist Drp1-docking at OMMs: Fis1, the role of which is still controversial in mammals [33,34]; Mff [35,36]; MiD51 and MiD49 [37]. In addition, other "less conventional" proteins can mediate Drp1 recruitment at OMM, and promote mitochondria fission, such as the cytoplasmic kinase leucine-rich-repeat kinase 2 (LRRK2) [38,39], the membrane trafficking and apoptosis regulator small Ras family member G-protein Rab32 [40,41] and the very recently discovered dynamin-2 (Dyn-2) [42].…”