MassIVE MSV000095767

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Hypermetabolism induced pantothenate depletion in MT-ATP6 neuropathy

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Description

Mitochondrial DNA mutations frequently result in mitochondrial dysfunction and energy deficits, compromising cellular and tissue functions. However, in some cases, bioenergetic deficits triggers a futile cycle of energy production and consumption to maintain cellular function, a phenomenon termed hypermetabolism. In this study, we used patient iPSC-derived motor neurons to investigate a truncating heteroplasmic mutation in the MT-ATP6 gene, which encodes a subunit of the proton pore of the ATP synthase. We successfully generated motor neurons with 50% mutation heteroplasmy, despite adverse effects on ATP synthase assembly. Through a combination of respirometry, metabolomic tracing, and proteomic analysis, we observed increased metabolic activity in mutant motor neurons, indicative of a hypermetabolic phenotype. This is the first study to explore hypermetabolism in neurons, revealing new significant implications of this state. This hypermetabolic state Hypermetabolism led to the reprioritization of the core metabolite acetyl-CoA and depletion of its precursor, resulting in the downregulation . We also observed the downregulation of epigenetic and SUMOylation pathways, likely as compensatory and adaptive mechanisms. Our findings suggest a link between mitochondrial dysfunction and SUMOylation, highlighting a potential new contributor to the mitochondrial hypermetabolic phenotype. [doi:10.25345/C5028PR2B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: mitochondria ; hypermetabolism ; MT-ATP6 ; heteroplasmy

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Principal Investigators:
(in alphabetical order) 		Ruben Torregrosa-Munumer, University of Helsinki, Finland
Submitting User: jkvist
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