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

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

Author information

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, Clayton, VIC Australia.
3
Metabolomics Australia, The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia.
4
Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.
5
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
6
Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia.
7
Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia. Electronic address: d.stojanovski@unimelb.edu.au.

Abstract

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

PMID:
28712726
DOI:
10.1016/j.molcel.2017.06.014
[Indexed for MEDLINE]
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