Invited Speaker Abstract 2018 Hunter Cell Biology Meeting

Senger’s syndrome associated mitochondrial acylglycerol kinase, is a subunit of the human TIM22 protein import complex (#44)

Yilin Kang 1 , David A. Stroud 2 , Michael J. Baker 1 , David P. De Souza 3 , Ann E. Frazier 4 5 , Michael Liem 6 , Dedreia Tull 3 , Suresh Mathivanan 6 , Malcolm J. McConville 3 , David R. Thorburn 4 5 , Michael T. Ryan 2 , Diana Stojanovski 1
  1. Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
  3. Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
  4. Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia
  5. Murdoch Children’s Research Institute, Royal Children’s Hospital and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia

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 Senger’s syndrome, which is characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance and lactic acidosis. We identified AGK as a subunit of the TIM22 protein import complex. TIM22 mediates import of mitochondrial carrier proteins, which facilitate the continuous flux of diverse metabolites, nucleotides and cofactors into and out of the mitochondrion, and are essential oxidative phosphorylation, the TCA cycle, fatty acid oxidation, protein synthesis and ion transport. AGK functions in a kinase-­independent manner to maintain the integrity of the TIM22 complex, where it facilitates the import/assembly of mitochondrial carrier proteins. Mitochondria isolated from Senger’s 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 TCA cycle in cells lacking AGK. Our identification of AGK as a bona fide subunit of TIM22 has provided an exciting link between protein import via TIM22 and mitochondrial disease.