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Mitochondrial DNA competition: starving out the mutant genome

Spinazzola, Antonella; Perez-Rodriguez, Diego; Ježek, Jan; Holt, Ian J; (2024) Mitochondrial DNA competition: starving out the mutant genome. Trends in Pharmacological Sciences 10.1016/j.tips.2024.01.011. (In press). Green open access

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Abstract

High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants. The underlying mechanisms are beginning to be clarified, and recent studies suggest that metabolic cues, including fuel availability, contribute to shaping mtDNA heteroplasmy. In the context of pathological mtDNAs, remodeling of nutrient metabolism supports mitochondria with deleterious mtDNAs and enables them to outcompete functional variants owing to a replicative advantage. The elevated nutrient requirement represents a mutant Achilles' heel because small molecules that restrict nutrient consumption or interfere with nutrient sensing can purge cells of deleterious mtDNAs and restore mitochondrial respiration. These advances herald the dawn of a new era of small-molecule therapies to counteract pathological mtDNAs.

Type: Article
Title: Mitochondrial DNA competition: starving out the mutant genome
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.tips.2024.01.011
Publisher version: http://dx.doi.org/10.1016/j.tips.2024.01.011
Language: English
Additional information: © 2024 The Authors. Published by Elsevier Ltd. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: mitochondrial DNA, heteroplasmy, 2-Deoxy-d-glucose, nutrient metabolism, nutrient signaling, epigenetic rewiring
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10188407
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