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.

• MeSH
• Apoptosis MeSH
• ATPases Associated with Diverse Cellular Activities MeSH
• Gene Knockdown Techniques MeSH
• GTP Phosphohydrolases metabolism   MeSH
• Humans MeSH
• Metalloendopeptidases metabolism   MeSH
• Mitochondrial Membranes metabolism   MeSH
• Mitochondrial Proteins MeSH
• Mitochondria metabolism   MeSH
• NADH, NADPH Oxidoreductases metabolism   MeSH
• Cell Proliferation * MeSH
• ATP-Dependent Proteases metabolism   MeSH
• Peptide Hydrolases metabolism   MeSH
• Protein Isoforms metabolism   MeSH
• Electron Transport Complex I MeSH
• Electron Transport Complex IV metabolism   MeSH
• Saccharomyces cerevisiae Proteins metabolism   MeSH
• Saccharomyces cerevisiae cytology   metabolism   MeSH
• Electron Transport * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ATPases Associated with Diverse Cellular Activities MeSH
• GTP Phosphohydrolases MeSH
• Metalloendopeptidases MeSH
• Mitochondrial Proteins MeSH
• NADH, NADPH Oxidoreductases MeSH
• NDUFB6 protein, human MeSH Browser
• OPA1 protein, human MeSH Browser
• ATP-Dependent Proteases MeSH
• Peptide Hydrolases MeSH
• Protein Isoforms MeSH
• Electron Transport Complex I MeSH
• Electron Transport Complex IV MeSH
• Saccharomyces cerevisiae Proteins MeSH
• YME1 protein, S cerevisiae MeSH Browser
• YME1L1 protein, human MeSH Browser