title: Restricted mitochondrial protein acetylation initiates mitochondrial autophagy.
abstract: Because nutrient-sensing nuclear and cytosolic acetylation mediates cellular autophagy, we investigated whether mitochondrial acetylation modulates mitochondrial autophagy (mitophagy). Knockdown of GCN5L1, a component of the mitochondrial acetyltransferase machinery, diminished mitochondrial protein acetylation and augmented mitochondrial enrichment of autophagy mediators. This program was disrupted by SIRT3 knockdown. Chronic GCN5L1 depletion increased mitochondrial turnover and reduced mitochondrial protein content and/or mass. In parallel, mitochondria showed blunted respiration and enhanced 'stress-resilience'. Genetic disruption of autophagy mediators Atg5 and p62 (also known as SQSTM1), as well as GCN5L1 reconstitution, abolished deacetylation-induced mitochondrial autophagy. Interestingly, this program is independent of the mitophagy E3-ligase Parkin (also known as PARK2). Taken together, these data suggest that deacetylation of mitochondrial proteins initiates mitochondrial autophagy in a canonical autophagy-mediator-dependent program and shows that modulation of this regulatory program has ameliorative mitochondrial homeostatic effects.
authors.affiliation: Center for Molecular Medicine, NHLBI, NIH, Bethesda, MD 20892, USA.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Webster
authors.forename: Iain
authors.initials: I
authors.lastname: Scott
authors.forename: Kim
authors.initials: K
authors.lastname: Han
authors.forename: Jian H
authors.initials: JH
authors.lastname: Li
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Lu
authors.forename: Mark V
authors.initials: MV
authors.lastname: Stevens
authors.forename: Daniela
authors.initials: D
authors.lastname: Malide
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Leigh
authors.initials: L
authors.lastname: Samsel
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Connelly
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Daniels
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Christian A
authors.initials: CA
authors.lastname: Combs
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000107:Acetylation; D000818:Animals; D001343:Autophagy; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C104378:BLOC1S1 protein, human; C000619640:BLOC1S1 protein, mouse; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D044767:Ubiquitin-Protein Ligases
keywords: Acetylation; GCN5L1; Mitochondrial autophagy; Parkin; SIRT3