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

Boris Pantic, Daniel Ives, Mara Mennuni, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Mikel Muñoz-Oreja, Marina Villar-Fernandez, Thanh-mai Julie Dang, Lodovica Vergani, Iain G. Johnston, Robert D. S. Pitceathly, Robert McFarland, Michael G. Hanna, Robert W. Taylor, Ian J. Holt () and Antonella Spinazzola ()
Additional contact information
Boris Pantic: Royal Free Campus
Daniel Ives: Royal Free Campus
Mara Mennuni: Royal Free Campus
Diego Perez-Rodriguez: Royal Free Campus
Uxoa Fernandez-Pelayo: Biodonostia Health Research Institute
Amaia Lopez de Arbina: Biodonostia Health Research Institute
Mikel Muñoz-Oreja: Biodonostia Health Research Institute
Marina Villar-Fernandez: Biodonostia Health Research Institute
Thanh-mai Julie Dang: Royal Free Campus
Lodovica Vergani: University of Padova
Iain G. Johnston: University of Bergen
Robert D. S. Pitceathly: UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery
Robert McFarland: Faculty of Medical Sciences Newcastle University
Michael G. Hanna: UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery
Robert W. Taylor: Faculty of Medical Sciences Newcastle University
Ian J. Holt: Royal Free Campus
Antonella Spinazzola: Royal Free Campus

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26829-0

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