期刊
MOLECULAR CELL
卷 69, 期 4, 页码 581-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.01.034
关键词
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资金
- Medical Research Council (MRC) [MC_UU_12022/7]
- MRC doctorate training (DTA studentship)
- Q3 European Union Horizon grant SyMBioSys MSCA-ITN-ETN [675585]
- Medical Research Council, UK [MC_U105697135]
- Biochemical and Biophysical Research Council [BB/L020874/1, BB/P018726/1]
- Wellcome Trust [097815/Z/11/Z, 093734/Z/10/Z]
- Medical Research Council [MC_UP_1201/4]
- Wellcome Trust [097815/Z/11/Z] Funding Source: Wellcome Trust
- BBSRC [BB/L020874/1] Funding Source: UKRI
- MRC [MC_UU_12022/7, MC_U105697135, MC_UU_12022/6, MC_UP_1201/4, MC_UU_00015/4] Funding Source: UKRI
- Medical Research Council [1499939, MC_U105697135, MC_UU_00015/4, MC_UU_12022/7, MC_UP_1201/4, MC_UU_12022/6] Funding Source: researchfish
- Marie Curie Actions (MSCA) [675585] Funding Source: Marie Curie Actions (MSCA)
The bioenergetics and molecular determinants of themetabolic response to mitochondrial dysfunction are incompletely understood, in part due to a lack of appropriate isogenic cellular models of primary mitochondrial defects. Here, we capitalize on a recently developed cell model with defined levels of m.8993T>G mutation heteroplasmy, mTUNE, to investigate the metabolic underpinnings of mitochondrial dysfunction. We found that impaired utilization of reduced nicotinamide adenine dinucleotide (NADH) by the mitochondrial respiratory chain leads to cytosolic reductive carboxylation of glutamine as a new mechanism for cytosol-confined NADH recycling supported by malate dehydrogenase 1 (MDH1). We also observed that increased glycolysis in cells with mitochondrial dysfunction is associated with increased cell migration in an MDH1-dependent fashion. Our results describe a novel link between glycolysis and mitochondrial dysfunction mediated by reductive carboxylation of glutamine.
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