Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations. Academic Article uri icon

Overview

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.

publication date

  • April 12, 2018

Research

keywords

  • DNA, Mitochondrial
  • Glutamine
  • Ketoglutaric Acids
  • Mitochondria
  • Mitochondrial Myopathies

Identity

PubMed Central ID

  • PMC5932217

Scopus Document Identifier

  • 85045107945

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2018.03.002

PubMed ID

  • 29657030

Additional Document Info

volume

  • 27

issue

  • 5