| First Author | Chen Q | Year | 2018 |
| Journal | Cell Metab | Volume | 27 |
| Issue | 5 | Pages | 1007-1025.e5 |
| PubMed ID | 29657030 | Mgi Jnum | J:263026 |
| Mgi Id | MGI:6159525 | Doi | 10.1016/j.cmet.2018.03.002 |
| Citation | Chen Q, et al. (2018) Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations. Cell Metab 27(5):1007-1025.e5 |
| abstractText | Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived alpha-ketoglutarate (alphaKG) 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 alphaKG 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, alphaKG oxidative flux prevails over reductive carboxylation. Furthermore, in a mouse model of mitochondrial myopathy, we show that increased oxidative alphaKG 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 alphaKG supplementation. Taken together, our findings provide a rationale for alphaKG supplementation as a therapeutic strategy for mitochondrial myopathies. |
