氧化磷酸化
线粒体DNA
生物
生物能学
谷氨酰胺
线粒体
焊剂(冶金)
生物化学
线粒体肌病
粒线体疾病
氨基酸
突变体
细胞生物学
基因
化学
有机化学
作者
Justin Chen,Kathryne Kirk,Yevgeniya I. Shurubor,Dazhi Zhao,Andrea J. Arreguin,Ifrah Shahi,Federica Valsecchi,Guido Primiano,Elizabeth L. Calder,Valerio Carelli,Travis T. Denton,M. Flint Beal,Steven S. Gross,Giovanni Manfredi,Marilena D'Aurelio
出处
期刊:Cell Metabolism
[Elsevier]
日期:2018-05-01
卷期号:27 (5): 1007-1025.e5
被引量:133
标识
DOI:10.1016/j.cmet.2018.03.002
摘要
Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation. Furthermore, in a mouse model of mitochondrial myopathy, we show that increased oxidative αKG flux in muscle arises from enhanced alanine synthesis and release into blood, concomitant with accelerated amino acid catabolism from protein breakdown. Importantly, in this mouse model of mitochondriopathy, muscle amino acid imbalance is normalized by αKG supplementation. Taken together, our findings provide a rationale for αKG supplementation as a therapeutic strategy for mitochondrial myopathies.
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