title: The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease.
abstract: Mitochondrial morphology is governed by the balance of mitochondrial fusion, mediated by mitofusins and optic atrophy 1 (OPA1), and fission, mediated by dynamin-related protein 1 (Drp1). Disordered mitochondrial dynamics alters metabolism, proliferation, apoptosis and mitophagy, contributing to human diseases, including neurodegenerative syndromes, pulmonary arterial hypertension (PAH), cancer and ischemia/reperfusion injury. Post-translational regulation of Drp1 (by phosphorylation and SUMOylation) is an established means of modulating Drp1 activation and translocation to the outer mitochondrial membrane (OMM). This review focuses on Drp1 adaptor proteins that also regulate fission. The proteins include fission 1 (Fis1), mitochondrial fission factor (Mff) and mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49, MiD51). Heterologous MiD overexpression sequesters inactive Drp1 on the OMM, promoting fusion; conversely, increased endogenous MiD creates focused Drp1 multimers that optimize OMM scission. The triggers that activate MiD-bound Drp1 in disease states are unknown; however, MiD51 has a unique capacity for ADP binding at its nucleotidyltransferase domain. Without ADP, MiD51 inhibits Drp1, whereas ADP promotes MiD51-mediated fission, suggesting a link between metabolism and fission. Confusion over whether MiDs mediate fusion (by sequestering inactive Drp1) or fission (by guiding Drp1 assembly) relates to a failure to consider cell types used and to distinguish endogenous compared with heterologous changes in expression. We speculate that endogenous MiDs serve as Drp1-binding partners that are dysregulated in disease states and may be important targets for inhibiting cell proliferation and ischemia/reperfusion injury. Moreover, it appears that the composition of the fission apparatus varies between disease states and amongst individuals. MiDs may be important targets for inhibiting cell proliferation and attenuating ischemia/reperfusion injury.
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Atkins
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
authors.forename: Asish
authors.initials: A
authors.lastname: Dasgupta
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
authors.forename: Kuang-Hueih
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada, K7L 3N6.
authors.forename: Jeff
authors.initials: J
authors.lastname: Mewburn
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada, K7L 3N6 stephen.archer@queensu.ca.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010445:Peptide Elongation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C561316:MIEF1 protein, human; C585230:MIEF2 protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D010445:Peptide Elongation Factors; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Smith–Magenis syndrome chromosome region candidate gene 7-like (SMCR7L); dynamin-related protein 1 (Drp1); fission 1 (Fis1); homoeostasis; mitochondria; mitochondrial dynamics proteins of 49 kDa and 51 kDa (MiD49 and MiD51); mitochondrial elongation factor 2 (MIEF2); mitochondrial fission factor (Mff)