Defining the mitochondrial function of acylglycerol kinase (AGK) associated with Sengers syndrome
Final Report Abstract
AGK is the mitochondrial acylglycerol kinase that generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. Mutations in AGK cause Sengers syndrome characterized by cataracts, hypertrophic cardiomyopathy and skeletal myopathy. However, molecular mechanisms of the mitochondrial pathology remain enigmatic. By identifying AGK interacting partners AGK was characterized as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with other subunits of the TIM22 complex, TIMM22 and TIMM29, and supports the import of a subset of multi-spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome.
Publications
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(2017) Acylglycerol Kinase Mutated in Sengers Syndrome Is a Subunit of the TIM22 Protein Translocase in Mitochondria. Molecular cell 67 (3) 471-483.e7
Vukotic, Milena; Nolte, Hendrik; König, Tim; Saita, Shotaro; Ananjew, Maria; Krüger, Marcus; Tatsuta, Takashi; Langer, Thomas
