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Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations.

Abstract：

: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.

journal_name

Cell Metab

journal_title

Cell metabolism

authors

Chen Q,Kirk K,Shurubor YI,Zhao D,Arreguin AJ,Shahi I,Valsecchi F,Primiano G,Calder EL,Carelli V,Denton TT,Beal MF,Gross SS,Manfredi G,D'Aurelio M

doi

10.1016/j.cmet.2018.03.002

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1007-1025.e5

issue

5

eissn

1550-4131

issn

1932-7420

pii

S1550-4131(18)30180-3

journal_volume

27

pub_type

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