2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA.
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DOI：
10.1038/s41467-021-26829-0
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发表时间：
2021-12-06
影响因子：
16.6
通讯作者：
Spinazzola A
中科院分区：
文献类型：
--
作者：
Pantic B;Ives D;Mennuni M;Perez-Rodriguez D;Fernandez-Pelayo U;Lopez de Arbina A;Muñoz-Oreja M;Villar-Fernandez M;Dang TJ;Vergani L;Johnston IG;Pitceathly RDS;McFarland R;Hanna MG;Taylor RW;Holt IJ;Spinazzola A
人类线粒体DNA（mtDNA）的病理变体通常与野生型分子共存，但驱动选择每种分子的因素尚不清楚。由于线粒体健康不利于疾病状态下功能性mtDNA的繁殖，我们试图创造有利的条件。葡萄糖和谷氨酰胺的消耗在mtDNA功能障碍中增加，因此我们针对携带致病性m.3243A>G变体的细胞使用2-脱氧-D-葡萄糖（2DG）或相关的5-硫代葡萄糖。在这里，我们表明这两种化合物都选择了野生型而不是突变型线粒体DNA，恢复了线粒体DNA的表达和呼吸。从机制上讲，2DG选择性地抑制突变mtDNA的复制;谷氨酰胺是关键的靶代谢物，因为它的撤回也抑制突变细胞中mtDNA的合成。此外，通过限制葡萄糖利用，2DG支持功能性mtDNA，因为当葡萄糖和谷氨酰胺缺乏时，葡萄糖驱动的呼吸对对照细胞中的mtDNA复制至关重要。因此，我们证明，线粒体健身决定代谢物的偏好mtDNA复制，因此，限制代谢物的可用性的干预措施可以抑制病理mtDNA，通过耦合线粒体健身和复制。在两种物种共存的细胞中，以病理分子为代价促进功能性线粒体DNA的繁殖一直是一个长期的目标。在这里，作者表明，限制葡萄糖和谷氨酰胺的可用性可以实现这一结果。
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. It has been a longstanding goal to promote the propagation of functional mitochondrial DNAs at the expense of pathological molecules in cells where the two species coexist. Here, the authors show that restricting the availability of glucose and glutamine can achieve this outcome.
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影响因子：
64.8
作者：
GOTO, Y;NONAKA, I;HORAI, S
通讯作者：
HORAI, S
影响因子：
6
作者：
MARIOTTI, C;SAVARESE, N;ZEVIANI, M
通讯作者：
ZEVIANI, M
DOI：
10.1073/pnas.92.14.6562
发表时间：
1995-07-03
影响因子：
11.1
作者：
DUNBAR, DR;MOONIE, PA;HOLT, IJ
通讯作者：
HOLT, IJ
影响因子：
30.8
作者：
Hill, Jahda H.;Chen, Zhe;Xu, Hong
通讯作者：
Xu, Hong
影响因子：
3.5
作者：
Holt, IJ;Dunbar, DR;Jacobs, HT
通讯作者：
Jacobs, HT