α-ketobutyrate links alterations in cystine metabolism to glucose oxidation in mtDNA mutant cells

Nicholas P. Lesner, Amrita S. Gokhale, Kalyani Kota, Ralph J. DeBerardinis, Prashant Mishra

Research output: Contribution to journalArticle

Abstract

Pathogenic mutations in the mitochondrial genome (mtDNA) impair organellar ATP production, requiring mutant cells to activate metabolic adaptations for survival. Understanding how metabolism adapts to clinically relevant mtDNA mutations may provide insight into cellular strategies for metabolic flexibility. In this study, we use 13C isotope tracing and metabolic flux analysis to investigate central carbon and amino acid metabolic reprogramming in isogenic cells containing mtDNA mutations. We identify alterations in glutamine and cystine transport which indirectly regulate mitochondrial metabolism and electron transport chain function. Metabolism of cystine can promote glucose oxidation through the transsulfuration pathway and the production of α-ketobutyrate. Intriguingly, activating or inhibiting α-ketobutyrate production is sufficient to modulate both glucose oxidation and mitochondrial respiration in mtDNA mutant cells. Thus, cystine-stimulated transsulfuration serves as an adaptive mechanism linking glucose oxidation and amino acid metabolism in the setting of mtDNA mutations.

Original languageEnglish (US)
Pages (from-to)157-167
Number of pages11
JournalMetabolic Engineering
Volume60
DOIs
StatePublished - Jul 2020

Keywords

  • Metabolic reprogramming
  • Transsulfuration
  • mtDNA mutations

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology

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