Crls1, or cardiolipin synthase 1, is crucial for mitochondrial cardiolipin biosynthesis, regulating phosphatidylglycerol remodeling [2,3]. Cardiolipin is essential for mitochondrial structure and function, and thus Crls1 is involved in maintaining mitochondrial integrity and processes like oxidative phosphorylation (OXPHOS) [1,2]. It may also be associated with lipid and seleno-amino acid metabolism and the MAPK signaling pathway [4]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying Crls1 function.

In KO mouse models, AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a cardiotoxin-induced muscle damage model, while AAV9-mCrls1-mediated overexpression improved it, indicating that age-dependent decrease in CRLS1 expression contributes to muscle loss in skeletal muscle myoblasts [1]. Deleterious variants in CRLS1 in human patients and KO cell lines led to cardiolipin deficiency, mitochondrial morphological and biogenesis impairment, and an autosomal recessive multi-system mitochondrial disease [2]. In hepatocyte-specific Crls1-knockout (Crls1-HKO) mice, high-fat diet-induced insulin resistance and hepatic steatosis were exacerbated, and Crls1 depletion aggravated the inflammatory response and fibrosis during non-alcoholic steatohepatitis (NASH) development. Mechanistically, CRLS1 suppresses activating transcription factor 3 (ATF3) expression and activity [3].

In conclusion, Crls1 is essential for maintaining mitochondrial function, muscle regeneration, and metabolism-related processes. Gene knockout models, especially in mice, have been instrumental in revealing its role in myopathy, mitochondrial diseases, and NASH. Understanding Crls1 function provides insights into the mechanisms of these diseases and potential therapeutic strategies [1,2,3].