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2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA

Lookup NU author(s): Professor Bobby McFarlandORCiD, Professor Robert Taylor

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Abstract

© 2021, The Author(s).Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication.

Publication metadata

Author(s): Pantic B, Ives D, Mennuni M, Perez-Rodriguez D, Fernandez-Pelayo U, Lopez de Arbina A, Munoz-Oreja M, Villar-Fernandez M, Dang T-MJ, Vergani L, Johnston IG, Pitceathly RDS, McFarland R, Hanna MG, Taylor RW, Holt IJ, Spinazzola A

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2021

Volume: 12

Issue: 1

Print publication date: 01/12/2021

Online publication date: 06/12/2021

Acceptance date: 18/10/2021

Date deposited: 07/01/2022

ISSN (electronic): 2041-1723

Publisher: Nature Research

URL: https://doi.org/10.1038/s41467-021-26829-0

DOI: 10.1038/s41467-021-26829-0

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