title: Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.
abstract: Accumulation of depolarized mitochondria within beta-cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a 'kiss and run' pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (delta psi(m)) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non-fusing mitochondria that were found to have reduced delta psi(m) and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1(K38A) or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre-proteolysis stage reveal that before autophagy mitochondria lose delta psi(m) and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Gilad
authors.initials: G
authors.lastname: Twig
authors.forename: Alvaro
authors.initials: A
authors.lastname: Elorza
authors.forename: Anthony J A
authors.initials: AJ
authors.lastname: Molina
authors.forename: Hibo
authors.initials: H
authors.lastname: Mohamed
authors.forename: Jakob D
authors.initials: JD
authors.lastname: Wikstrom
authors.forename: Gil
authors.initials: G
authors.lastname: Walzer
authors.forename: Linsey
authors.initials: L
authors.lastname: Stiles
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Haigh
authors.forename: Steve
authors.initials: S
authors.lastname: Katz
authors.forename: Guy
authors.initials: G
authors.lastname: Las
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Py
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Jude T
authors.initials: JT
authors.lastname: Deeney
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Corkey
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D007328:Insulin; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse