Schober 2021 Sci Adv

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Schober FA, Moore D, Atanassov I, Moedas MF, Clemente P, Végvári Á, Fissi NE, Filograna R, Bucher AL, Hinze Y, The M, Hedman E, Chernogubova E, Begzati A, Wibom R, Jain M, Nilsson R, Käll L, Wedell A, Freyer C, Wredenberg A (2021) The one-carbon pool controls mitochondrial energy metabolism via complex I and iron-sulfur clusters. Sci Adv 7:eabf0717.

» PMID: 33608280 Open Access

Schober Florian A, Moore David, Atanassov Ilian, Moedas Marco F, Clemente Paula, Vegvari Akos, Fissi Najla El, Filograna Roberta, Bucher Anna-Lena, Hinze Yvonne, The Matthew, Hedman Erik, Chernogubova Ekaterina, Begzati Arjana, Wibom Rolf, Jain Mohit, Nilsson Roland, Kaell Lukas, Wedell Anna, Freyer Christoph, Wredenberg Anna (2021) Sci Adv

Abstract: Induction of the one-carbon cycle is an early hallmark of mitochondrial dysfunction and cancer metabolism. Vital intermediary steps are localized to mitochondria, but it remains unclear how one-carbon availability connects to mitochondrial function. Here, we show that the one-carbon metabolite and methyl group donor S-adenosylmethionine (SAM) is pivotal for energy metabolism. A gradual decline in mitochondrial SAM (mitoSAM) causes hierarchical defects in fly and mouse, comprising loss of mitoSAM-dependent metabolites and impaired assembly of the oxidative phosphorylation system. Complex I stability and iron-sulfur cluster biosynthesis are directly controlled by mitoSAM levels, while other protein targets are predominantly methylated outside of the organelle before import. The mitoSAM pool follows its cytosolic production, establishing mitochondria as responsive receivers of one-carbon units. Thus, we demonstrate that cellular methylation potential is required for energy metabolism, with direct relevance for pathophysiology, aging, and cancer.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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