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

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.

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

“…An example is AGK, encoding a mitochondrial inner membrane lipid modifying acylglycerol kinase, in which defects lead to Sengers syndrome (MIM 212350) (48). Recent studies show that AGK also functions in the carrier protein import pathway of mitochondria, independent of its kinase activity (56,57). Likewise, mutations in the mitochondrial ATP/ADP transporter (ANT1), encoded by SLC25A4, can impact not only on the ADP/ATP ratio but also on mtDNA homeostasis by altering mitochondrial dNTP equilibrium (58).…”

“…f While classified as having a role in mitochondrial protein import, AGK and DNAJC19 are also implicated in mitochondrial lipid homeostasis (56,57,59). g Although classified as a member of the carrier family, SLC25A46 localizes to the mitochondrial outer membrane where it functions in mitochondrial cristae architecture (61).…”

Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

“…4I, right panel; Supplementary Table 4) whereas complex I, III and IV subunits were not strongly enriched. The enrichment of TMEM186 with the TIM22 machinery (TIM22, TIM29, AGK, small TIMs) may be due to TMEM186 using the TIM22 import pathway for membrane integration (Callegari et al, 2016;Kang et al, 2016;Kang et al, 2018;Kang et al, 2017;Vukotic et al, 2017) as well as overexpression of the Flag tagged protein. Mitochondria from cells expressing TMEM186 Flag were subjected to alkali extraction (Na2CO3) followed by SDS-PAGE and western blot analysis.…”

News and views

“…A defect in the latter function is largely responsible for the disease in patients with mutations in the HSD17B10 . Two back-to-back published articles in Molecular Cell now report another elegant example of protein moonlighting in an inborn error of metabolism (Kang et al 2017; Vukotic et al 2017). Sengers syndrome is a mitochondrial disorder associated with a deficiency of the mitochondrial carrier ANT1 (SLC25A4; adenine nucleotide translocator).…”

“…Given the importance of phospholipid metabolism and remodeling for mitochondrial function, Mayr et al speculated that AGK affects ANT1 stability via effects on mitochondrial phospholipid metabolism (Mayr et al 2012). The teams of Stojanovski and Langer now show that a major function of AGK is as a subunit of the TIM22 protein import complex (Kang et al 2017; Vukotic et al 2017). This protein complex is involved in the import of transmembrane proteins such as mitochondrial carrier family members (SLC25A family) from the cytosol into the mitochondrial inner membrane.…”