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- W3035719293 abstract "ABSTRACT 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. This differential substrate vulnerability is consistent with the half-lives for mitochondrial proteins, and with the abundance of Fe-S clusters in proteins of different substrate oxidation pathways. Though cardiac contractility was preserved, likely due to sustained β-oxidation, a stress response was stimulated, characterized by activated mTORC1 and the p-eIF2α/ATF4 axis. Indeed, global protein translation was lower, which may account for a decrease in FXN-depleted hearts, and would help to lower ADP demand, which would be protective. 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." @default.
- W3035719293 created "2020-06-19" @default.
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- W3035719293 date "2020-06-12" @default.
- W3035719293 modified "2023-09-23" @default.
- W3035719293 title "Substrate-dependent suppression of oxidative phosphorylation in the Frataxin-depleted heart" @default.
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