CRLS1 (cardiolipin synthase 1) catalyzes cardiolipin synthesis by transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol, a critical reaction localized to mitochondrial membranes 1. Cardiolipin is essential for maintaining mitochondrial structural integrity and functional dynamics under both optimal and stress conditions 1. CRLS1 dysfunction has significant disease implications. Biallelic CRLS1 variants cause autosomal recessive mitochondrial disease presenting as progressive encephalopathy, with additional features including bull's eye maculopathy, auditory neuropathy, cardiac defects, and diabetes insipidus 1. Patient-derived fibroblasts showed impaired mitochondrial morphology, biogenesis, and reduced cardiolipin levels with elevated phosphatidylglycerol accumulation 1. CRLS1 expression correlates with disease protection in multiple contexts. High CRLS1 expression associates with improved overall survival in non-small cell lung cancer patients 2. CRLS1 downregulation promotes nonalcoholic fatty liver disease (NASH) through activating transcription factor 3 (ATF3), while CRLS1 overexpression attenuates hepatic steatosis and inflammation 3. Therapeutically, promoting cardiolipin synthesis via CRLS1 upregulation offers promise for Parkinson's disease prevention by enhancing mitochondrial homeostasis and dopaminergic neuron survival 4, and for diabetic nephropathy treatment through the UCP1/ARX/CRLS1 axis 5.