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

Mol Cell. 2017 Aug 3;67(3):457-470.e5. doi: 10.1016/j.molcel.2017.06.014. Epub 2017 Jul 14.


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.

Keywords: AGK; Sengers syndrome; TCA cycle; TIM22 complex; acylglycerol kinase; lipid metabolism; mitochondria; mitochondrial carrier proteins; protein transport.

MeSH terms

  • Cardiomyopathies / enzymology*
  • Cardiomyopathies / genetics
  • Cataract / enzymology*
  • Cataract / genetics
  • Citric Acid Cycle
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitochondria / enzymology*
  • 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
  • Transfection


  • Mitochondrial Membrane Transport Proteins
  • Multiprotein Complexes
  • AGK protein, human
  • Phosphotransferases (Alcohol Group Acceptor)

Supplementary concepts

  • Cataract and cardiomyopathy