title: A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance.
abstract: Damaged mitochondria pose a lethal threat to cells that necessitates their prompt removal. The currently recognized mechanism for disposal of mitochondria is autophagy, where damaged organelles are marked for disposal via ubiquitylation by Parkin. Here we report a novel pathway for mitochondrial elimination, in which these organelles undergo Parkin-dependent sequestration into Rab5-positive early endosomes via the ESCRT machinery. Following maturation, these endosomes deliver mitochondria to lysosomes for degradation. Although this endosomal pathway is activated by stressors that also activate mitochondrial autophagy, endosomal-mediated mitochondrial clearance is initiated before autophagy. The autophagy protein Beclin1 regulates activation of Rab5 and endosomal-mediated degradation of mitochondria, suggesting cross-talk between these two pathways. Abrogation of Rab5 function and the endosomal pathway results in the accumulation of stressed mitochondria and increases susceptibility to cell death in embryonic fibroblasts and cardiac myocytes. These data reveal a new mechanism for mitochondrial quality control mediated by Rab5 and early endosomes.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Babette C
authors.initials: BC
authors.lastname: Hammerling
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Rita H
authors.initials: RH
authors.lastname: Najor
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Melissa Q
authors.initials: MQ
authors.lastname: Cortez
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Shires
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Leonardo J
authors.initials: LJ
authors.lastname: Leon
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Gonzalez
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Boassa
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Phan
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thor
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Jimenez
authors.affiliation: Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Richard N
authors.identifier: 0000-0003-1395-9694
authors.initials: RN
authors.lastname: Kitsis
authors.affiliation: Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.affiliation: Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.affiliation: Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive 0758, La Jolla, California 92093, USA.
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Gustafsson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005347:Fibroblasts; D055785:Gene Knockdown Techniques; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063306:Mitophagy / Q000502:physiology*; D032383:Myocytes, Cardiac; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C512829:Becn1 protein, rat; D056827:Endosomal Sorting Complexes Required for Transport; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D020696:rab5 GTP-Binding Proteins