Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex

• Published in: Molecular cell Vol. 67; no. 3; pp. 457 - 470.e5
• Main Authors: Kang, Yilin, Stroud, David A., Baker, Michael J., De Souza, David P., Frazier, Ann E., Liem, Michael, Tull, Dedreia, Mathivanan, Suresh, McConville, Malcolm J., Thorburn, David R., Ryan, Michael T., Stojanovski, Diana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2017
• Subjects: acylglycerol kinase; AGK; Cardiomyopathies - enzymology; Cardiomyopathies - genetics; Cataract - enzymology; Cataract - genetics; Citric Acid Cycle; Genetic Predisposition to Disease; HEK293 Cells; HeLa Cells; Humans; lipid metabolism; mitochondria; Mitochondria - enzymology; mitochondrial carrier proteins; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Multiprotein Complexes; Mutation; Phenotype; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Stability; Protein Transport; Sengers syndrome; TCA cycle; TIM22 complex; Transfection; protein transport; mitochondrial carrier proteins; AGK; mitochondria; TCA cycle; lipid metabolism; Sengers syndrome; TIM22 complex; acylglycerol kinase
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.06.014

Acylglycerol kinase (AGK) is a mitochondrial lipid kinase that catalyzes the phosphorylation of monoacylglycerol and diacylglycerol to lysophosphatidic acid and phosphatidic acid, respectively. Mutations in AGK cause Sengers syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Here we identified AGK as a subunit of the mitochondrial TIM22 protein import complex. We show that AGK functions in a kinase-independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import and assembly of mitochondrial carrier proteins. Mitochondria isolated from Sengers syndrome patient cells and tissues show a destabilized TIM22 complex and defects in the biogenesis of carrier substrates. Consistent with this phenotype, we observe perturbations in the tricarboxylic acid (TCA) cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 provides an exciting and unexpected link between mitochondrial protein import and Sengers syndrome. [Display omitted] •Dysfunction in the mitochondrial acylglycerol kinase, AGK, causes Sengers syndrome•AGK is a subunit of the TIM22 complex, which imports mitochondrial carrier proteins•AGK has kinase-independent and kinase-dependent functions•The TIM22 complex and carrier import are affected in Sengers syndrome cells and tissues Sengers syndrome is a mitochondrial disorder caused by mutations in the lipid kinase AGK. Kang et al. show that AGK is a subunit of the mitochondrial TIM22 complex, where it functions in the import of carrier proteins in a kinase-independent manner. These findings link mitochondrial protein import to Sengers syndrome.