Friedreich’s ataxia (FRDA) is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remain poorly understood, though are expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels, and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97%-FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN depleted heart can suppress a major ATP demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

中文翻译：

---

心脏对 Frataxin 耗竭的适应：有证据表明综合应激反应可以超过 mTORC1 激活

弗里德赖希共济失调 (FRDA) 是一种由 frataxin (FXN) 消耗引起的遗传性疾病，这是一种铁硫簇 (ISC) 生物发生所需的线粒体蛋白。心功能不全是导致死亡的主要原因。然而，发病机制，更一般地说，心脏如何适应 FXN 损失，仍然知之甚少，尽管预计与能量不足有关。我们修改了可诱导 FXN 耗竭的转基因 (TG) 小鼠模型，该模型允许在不同 FXN 水平下对心脏进行表型评估，并专注于底物特异性生物能量学和压力信号传导。当 TG 心脏中的 FXN 蛋白为正常值的 17% 时，生物能量学和信号传导与对照没有不同。8 周后，当 FXN 在心脏中消耗约 97% 时，TG 心脏质量和心肌细胞横截面积减少，没有纤维化或细胞凋亡的证据。mTORC1 信号被激活，整合的应激反应也被激活，这可以通过 eIF2α 相对于总 eIF2α 更大的磷酸化和蛋白质翻译减少来证明。我们将这些结果解释为表明，在 TG 心脏中，合成代谢刺激受到 eIF2α 磷酸化的限制。在 97%-FXN 耗尽的心脏中，心脏收缩力得以维持，这可能是由于 β-氧化的意外保存，尽管丙酮酸氧化较低。生物能量学的改变与线粒体蛋白质组的变化相匹配，包括含 ISC 的蛋白质丰度的不均匀减少。总而言之，这些发现表明，FXN 耗尽的心脏可以抑制主要的 ATP 需求过程，例如蛋白质翻译，连同一些 β-氧化的保留，可能是适应性的，