Cardiomyopathy in a c.1528G>C Hadha mouse is associated with cardiac tissue lipotoxicity and altered cardiolipin species.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a metabolic disorder caused by the loss of LCHAD enzymatic activity in the α-subunit of the trifunctional protein (TFPα), leading to impaired fatty acid oxidation (FAO). Patients with LCHADD often develop dilated cardiomyopathy. A previously unrecognized enzymatic function of TFPα as monolysocardiolipin acyltransferase (MLCL-AT) has been implicated in cardiolipin remodeling, crucial for mitochondrial cristae integrity. However, it remains unclear whether the common pathogenic variant c.1528G>C in HADHA impairs MLCL-AT activity in TFPα. In this study, we investigated whether cardiac cardiolipin profiles are altered in LCHADD and explored potential pathophysiological mechanisms, including heart lipid accumulation, changes in the cardiolipin synthesis pathway, and mitochondrial dynamics, utilizing a murine model of LCHADD carrying c.1528G>C variant that mimics the cardiomyopathy observed in humans. LCHADD mice developed eccentric hypertrophic cardiomyopathy from 3- to 12 months of age. 12-month-old LCHADD hearts exhibited altered cardiolipin profiles and increased oxidized cardiolipin. LCHADD hearts had higher lipid content, and the shift in fatty acid profile mirrored the shift in cardiolipin profile compared to wild-type controls, suggesting altered cardiolipin composition in LCHADD may be a reflection of accumulated lipids caused by lower FAO. No differential expression of cardiolipin synthesis and remodeling pathway enzymes was observed, suggesting minimal impact of the c.1528G>C variant on cardiolipin remodeling pathway. LCHADD hearts showed an altered ratio of OPA1 isoforms, and mitochondria with swelling and disorganized cristae were present. These findings suggest that altered fatty acid, cardiolipin profiles, and mitochondrial dynamics may contribute to LCHADD cardiomyopathy, warranting further studies.