Department of Molecular Biosciences, University of California, Davis, CA, USA.
Department of Internal Medicine, University of California, Davis, CA, USA.
Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4.
Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxn::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.
弗里德赖希共济失调（FA）是一种常染色体隐性疾病，由线粒体中 frataxin（FXN）表达减少引起，其致死成分是心肌病。使用条件性 Fxn::MCK-Cre 敲除（Fxn-cKO）小鼠模型，我们发现心力衰竭进展存在显著的性别差异，Fxn-cKO 雄性表现出更差的心脏表型、低生存率、肾脏和生殖器官缺陷。这些差异可能归因于 Fxn-cKO 雄性体内睾酮的下降。睾酮的减少与参与胆固醇向线粒体转移的蛋白表达减少有关：外线粒体膜上的 StAR 和 TSPO，以及内线粒体膜上的胆固醇侧链裂解酶 P450scc 和亚铁氧化还原蛋白。Fxn-cKO 雄性中兴奋-收缩偶联蛋白（L 型钙通道、RyR2、SERCA2、磷酸化肌球蛋白轻链和 CaMKIIδ）的表达显著降低更多。这是第一项广泛研究 FA 小鼠模型心脏钙信号转导损伤中性别二态性的研究。
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