Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations
| Autor: | Steven S. Gross, Valerio Carelli, Ifrah Shahi, Yevgeniya I. Shurubor, Andrea J. Arreguin, Elizabeth L. Calder, Dazhi Zhao, M. Flint Beal, Qiuying Chen, Guido Primiano, Kathryne Kirk, Marilena D'Aurelio, Travis T. Denton, Giovanni Manfredi, Federica Valsecchi |
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| Přispěvatelé: | Chen, Qiuying, Kirk, Kathryne, Shurubor, Yevgeniya I., Zhao, Dazhi, Arreguin, Andrea J., Shahi, Ifrah, Valsecchi, Federica, Primiano, Guido, Calder, Elizabeth L., Carelli, Valerio, Denton, Travis T., Beal, M. Flint, Gross, Steven S., Manfredi, Giovanni, D'Aurelio, Marilena |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Mitochondrial DNA Physiology Glutamine glutamate Oxidative phosphorylation Mitochondrion DNA Mitochondrial Oxidative Phosphorylation Mice 03 medical and health sciences Mitochondrial myopathy medicine Animals Humans skeletal muscle Molecular Biology anaplerosi Alanine Catabolism Chemistry Mitochondrial Myopathies Cell Biology Metabolism medicine.disease OXPHOS dysfunction Adaptation Physiological Mitochondria Cell biology mitochondrial disease Disease Models Animal α-ketoglutarate 030104 developmental biology Mutation Ketoglutaric Acids Energy Metabolism metabolism Flux (metabolism) myopathy HeLa Cells |
| Zdroj: | Cell Metabolism. 27:1007-1025.e5 |
| ISSN: | 1550-4131 |
| Popis: | 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. Chen et al. show that patient cells with mtDNA mutations and a mouse model of mitochondrial myopathy have compensatory glutamine-derived anaplerotic flux that provides αKG to the TCA cycle to enable mutant cell survival. The metabolic fate of αKG (oxidative versus reductive) depends on the severity of OXPHOS impairment. |
| Databáze: | OpenAIRE |
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