Crls1, or cardiolipin synthase 1, is crucial for mitochondrial cardiolipin biosynthesis, regulating phosphatidylglycerol remodeling [3,4]. Cardiolipin is essential for mitochondrial structure and function, and thus Crls1 is involved in maintaining mitochondrial integrity, oxidative phosphorylation (OXPHOS), and mitochondrial biogenesis [2,3]. It may also be associated with lipid metabolism-related pathways [4,5]. Genetic models, such as knockout mouse models, are valuable for studying its functions.

Genetic ablation of Crls1 suppresses canonical and noncanonical inflammasome-mediated mitochondrial damage, pyroptosis, and inflammatory cytokine release, indicating its role in the gasdermin D-related pyroptosis pathway [1]. In a mouse model of cardiotoxin-induced muscle damage, AAV9-shCrls1-mediated downregulation of Crls1 impairs muscle regeneration, while AAV9-mCrls1-mediated overexpression improves it, highlighting its significance in age-related muscle deterioration and myogenesis [2]. Hepatocyte-specific Crls1-knockout (Crls1-HKO) mice show exacerbated insulin resistance, hepatic steatosis, inflammation, and fibrosis during non-alcoholic steatohepatitis (NASH) development, suggesting Crls1 ameliorates NASH by inhibiting the expression and activity of activating transcription factor 3 (ATF3) [4].

In conclusion, Crls1 is essential for maintaining mitochondrial function and integrity, and its role extends to processes like pyroptosis, muscle regeneration, and NASH development. The use of Crls1 knockout and conditional knockout mouse models has provided key insights into its functions in these disease-related biological processes, contributing to a better understanding of the underlying mechanisms and potentially paving the way for novel therapeutic strategies.