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.

中文翻译：

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线粒体DNA竞争：饥饿突变基因组

高水平的致病性线粒体 DNA (mtDNA) 变异会导致严重的遗传疾病，而此类突变体的积累也可能导致常见疾病。因此，针对这些突变体进行选择是线粒体医学的主要目标。尽管突变体 mtDNA 可以随机漂移，但越来越多的证据表明，主动力量在选择和对抗 mtDNA 变体中发挥着作用。潜在的机制开始被阐明，最近的研究表明，包括燃料可用性在内的代谢线索有助于塑造线粒体 DNA 异质性。在病理性 mtDNA 的背景下，营养代谢的重塑支持具有有害 mtDNA 的线粒体，并使它们能够凭借复制优势战胜功能性变异。营养需求升高代表了突变体的致命弱点，因为限制营养消耗或干扰营养感应的小分子可以清除细胞中有害的线粒体DNA并恢复线粒体呼吸。这些进展预示着对抗病理性线粒体 DNA 的小分子疗法新时代的到来。