Cesar Vasquez, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeova, Lauren Anderson-Pullinger, Nadan Wang, Erin L Seifert
bioRxiv 2020.06.12.148361; doi:10.1101/2020.06.12.148361
Friedreich's ataxia is an inherited disorder caused by depletion of frataxin (Fxn), a mitochondrial protein involved in iron-sulfur cluster biogenesis. Cardiac dysfunction is the main cause of death; pathogenesis remains poorly understood but is expected to be linked to an energy deficit. In mice with adult-onset Fxn loss, bioenergetics analysis of heart mitochondria revealed a time- and substrate-dependent decrease in oxidative phosphorylation (oxphos). Oxphos was lower with substrates that depend on Complex I and II, but preserved for lipid substrates, especially through electron entry into Complex III via the electron transfer flavoprotein dehydrogenase. This differential substrate vulnerability is consistent with the half-lives for mitochondrial proteins. Cardiac contractility was preserved, likely due to sustained β-oxidation. Yet, a stress response was stimulated, characterized by activated mTORC1 and the p-eIF2α/ATF4 axis. This study exposes an unrecognized mechanism that maintains oxphos in the Fxn-depleted heart. The stress response that nonetheless occurs suggests energy deficit-independent pathogenesis.
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