Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
Cell Metab. 2018 May 1;27(5):1007-1025.e5. doi: 10.1016/j.cmet.2018.03.002. Epub 2018 Apr 12.
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.
利用分子、生化和非靶向稳定同位素示踪方法，我们确定了一种以前未被重视的谷氨酰胺衍生的α-酮戊二酸（αKG）能量生成回补途径，对于携带人类疾病相关氧化磷酸化缺陷的线粒体 DNA（mtDNA）突变细胞至关重要。用 αKG 补充刺激这种通量，使各种 mtDNA 突变细胞在其他致命的必需氧化条件下能够存活。引人注目的是，我们证明了当 mtDNA 突变细胞中的剩余线粒体呼吸超过对照水平的 45%时，αKG 氧化通量优先于还原羧化。此外，在一种线粒体肌病的小鼠模型中，我们发现肌肉中氧化的 αKG 通量的增加源于丙氨酸合成和释放到血液中的增加，同时伴随着蛋白质分解引起的氨基酸分解代谢加速。重要的是，在这种线粒体疾病的小鼠模型中，αKG 补充使肌肉氨基酸失衡得到了纠正。总之，我们的研究结果为 αKG 补充作为线粒体肌病的治疗策略提供了依据。
