Eke Chibuike, Babcock Shannon, Gaston Garen, Elizondo Gabriela, Chung Hak, Asal Ayah, Chatfield Kathryn C, Sparagna Genevieve C, DeBarber Andrea E, Packwood William, Lindner Jonathan R, Gillingham Melanie B
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado, USA; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Lipid Res. 2025 Mar 29;66(5):100792. doi: 10.1016/j.jlr.2025.100792.
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.
长链3-羟基酰基辅酶A脱氢酶缺乏症（LCHADD）是一种代谢紊乱疾病，由三功能蛋白（TFPα）α亚基中LCHAD酶活性丧失引起，导致脂肪酸氧化（FAO）受损。LCHADD患者常发展为扩张型心肌病。TFPα作为单赖氨酸心磷脂酰基转移酶（MLCL-AT）的一种先前未被认识的酶功能与心磷脂重塑有关，这对线粒体嵴的完整性至关重要。然而，尚不清楚HADHA中常见的致病变体c.1528G>C是否会损害TFPα中的MLCL-AT活性。在本研究中，我们利用携带c.1528G>C变体的LCHADD小鼠模型（该模型模拟人类中观察到的心肌病），研究了LCHADD中心脏心磷脂谱是否改变，并探索了潜在的病理生理机制，包括心脏脂质积累、心磷脂合成途径变化和线粒体动力学。LCHADD小鼠在3至12月龄时出现离心性肥厚型心肌病。12月龄的LCHADD心脏表现出心磷脂谱改变和氧化心磷脂增加。与野生型对照相比，LCHADD心脏的脂质含量更高，脂肪酸谱的变化反映了心磷脂谱的变化，这表明LCHADD中心磷脂组成的改变可能是FAO降低导致脂质积累的反映。未观察到心磷脂合成和重塑途径酶的差异表达，这表明c.1528G>C变体对心磷脂重塑途径的影响最小。LCHADD心脏显示OPA1同工型比例改变，并且存在线粒体肿胀和嵴紊乱的情况。这些发现表明，脂肪酸、心磷脂谱和线粒体动力学的改变可能导致LCHADD心肌病，值得进一步研究。
