AGK, or acylglycerol kinase, is a subunit of the translocase of the mitochondrial inner membrane 22 (TIM22) protein import complex. It plays a role in maintaining mitochondrial integrity, lipid metabolism, and is involved in several signaling pathways. Mutations in AGK are the leading cause of Sengers syndrome, highlighting its biological importance. Genetic models, such as gene knockout (KO) mouse models, have been crucial for studying its functions [1,2,3,4].

In hepatic-specific AGK-deficient mice, AGK deficiency led to severe liver damage, lipid accumulation, and aggravated non-alcoholic steatohepatitis (NASH) symptoms induced by certain diets. This was due to hepatic mitochondrial dysfunction, as AGK interacts with mitochondrial respiratory chain complex I subunits to regulate mitochondrial fatty acid metabolism [1]. Megakaryocyte/platelet-specific AGK-deficient mice developed thrombocytopenia and splenomegaly, mainly due to inefficient bone marrow thrombocytopoiesis and excessive extramedullary hematopoiesis, indicating a role of AGK in megakaryocyte development and platelet biogenesis [4].

In conclusion, AGK is essential for maintaining mitochondrial function, especially in relation to mitochondrial respiratory chain complex I, and plays a role in processes like NASH development and thrombocytopoiesis. Studies using AGK KO mouse models have provided key insights into these functions, which may be relevant for understanding and treating related diseases such as NASH and thrombocytopenia [1,4].

References:

1. Ding, Nan, Wang, Kang, Jiang, Haojie, Xu, Yanyan, Liu, Junling. 2022. AGK regulates the progression to NASH by affecting mitochondria complex I function. In Theranostics, 12, 3237-3250. doi:10.7150/thno.69826. https://pubmed.ncbi.nlm.nih.gov/35547757/

2. Fan, Peng, Yang, Kun-Qi, Han, Bing, Qin, Xiu-Chuan, Tian, Tao. 2023. A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy. In Pediatric research, 94, 683-690. doi:10.1038/s41390-023-02515-3. https://pubmed.ncbi.nlm.nih.gov/36759750/

3. Wu, Chen-Han Wilfred, Caha, Martin, Smoot, Leslie, Sacharow, Stephanie, Bodamer, Olaf. 2023. Sengers syndrome and AGK-related disorders - Minireview of phenotypic variability and clinical outcomes in molecularly confirmed cases. In Molecular genetics and metabolism, 139, 107626. doi:10.1016/j.ymgme.2023.107626. https://pubmed.ncbi.nlm.nih.gov/37354892/

4. Jiang, Haojie, Yu, Zhuo, Ding, Nan, Xu, Yanyan, Liu, Junling. . The role of AGK in thrombocytopoiesis and possible therapeutic strategies. In Blood, 136, 119-129. doi:10.1182/blood.2019003851. https://pubmed.ncbi.nlm.nih.gov/32202634/