Acylglycerol kinase (AGK) is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism, plays an important role in the assembly of adenine nucleotide translocator (ANT), an essential component of the oxidative phosphorylation in mitochondria, and is also involved in mitochondrial protein transport, glycolysis, and thrombocytopoiesis.
AGK can act as a lipid kinase to catalyze the phosphorylation of diacylglycerol (DAG) and monoacylglycerol (MAG) to phosphatidic acid (PA) and lysophosphatidic acid (LPA), respectively. Both PA and LPA can act as signalling molecules and participate in phospholipid synthesis, which is essential to maintain mitochondrial structure and function.
Independently of its lipid kinase activity and its role in lipid metabolism stability, AGK acts as a subunit of the mitochondrial translocase of the inner membrane 22 (TIM22) complex, which is responsible for the translocation of transmembrane proteins from the cytoplasm into the mitochondrial interior and their insertion into the mitochondrial inner membrane via the formation of a twin-pore translocase that harnesses membrane potential as the external driving force. In the inner mitochondrial membrane, PA synthetises cardiolipin (CL), a mitochondria-specific phospholipid. CL plays a crucial role in the maintenance of these large protein complexes, including electron transport chain complexes and the protein import machinery of the inner membrane.
The onset of the disease at birth is likely associated with protein-truncating variants such as nonsense, frameshift, splice acceptor, and splice donor mutations. Although, frameshift and splicing defects were identified in patients with a later onset. Moreover, it seems homozygous variants frequently lead to a fatal prognosis of Sengers syndrome, while patients with compound heterozygous variants might live longer.
AGK