title: YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation.
abstract: Mitochondrial ATPases associated with diverse cellular activities (AAA) proteases are involved in the quality control and processing of inner-membrane proteins. Here we investigate the cellular activities of YME1L, the human orthologue of the Yme1 subunit of the yeast i-AAA complex, using stable short hairpin RNA knockdown and expression experiments. Human YME1L is shown to be an integral membrane protein that exposes its carboxy-terminus to the intermembrane space and exists in several complexes of 600-1100 kDa. The stable knockdown of YME1L in human embryonic kidney 293 cells led to impaired cell proliferation and apoptotic resistance, altered cristae morphology, diminished rotenone-sensitive respiration, and increased susceptibility to mitochondrial membrane protein carbonylation. Depletion of YME1L led to excessive accumulation of nonassembled respiratory chain subunits (Ndufb6, ND1, and Cox4) in the inner membrane. This was due to a lack of YME1L proteolytic activity, since the excessive accumulation of subunits was reversed by overexpression of wild-type YME1L but not a proteolytically inactive YME1L variant. Similarly, the expression of wild-type YME1L restored the lamellar cristae morphology of YME1L-deficient mitochondria. Our results demonstrate the importance of mitochondrial inner-membrane proteostasis to both mitochondrial and cellular function and integrity and reveal a novel role for YME1L in the proteolytic regulation of respiratory chain biogenesis.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Charles University in Prague and General University Hospital in Prague, 12808 Prague 2, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Stiburek
authors.forename: Jana
authors.initials: J
authors.lastname: Cesnekova
authors.forename: Olga
authors.initials: O
authors.lastname: Kostkova
authors.forename: Daniela
authors.initials: D
authors.lastname: Fornuskova
authors.forename: Kamila
authors.initials: K
authors.lastname: Vinsova
authors.forename: Laszlo
authors.initials: L
authors.lastname: Wenchich
authors.forename: Josef
authors.initials: J
authors.lastname: Houstek
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
mesh_terms: D049069:ATP-Dependent Proteases / Q000378:metabolism; D000074183:ATPases Associated with Diverse Cellular Activities; D017209:Apoptosis; D049109:Cell Proliferation; D004579:Electron Transport; D042967:Electron Transport Complex I; D003576:Electron Transport Complex IV / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D029701:Saccharomyces cerevisiae Proteins; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D010447:Peptide Hydrolases; D049069:ATP-Dependent Proteases; C082702:YME1 protein, S cerevisiae; D008666:Metalloendopeptidases; C410807:YME1L1 protein, human; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D042967:Electron Transport Complex I; C527690:NDUFB6 protein, human