Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction

Hum Mol Genet. 2021 Oct 13;30(21):2012-2026. doi: 10.1093/hmg/ddab168.

Abstract

Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Biological*
  • Amino Acids / metabolism
  • Animals
  • Cell Survival / genetics
  • Citric Acid Cycle
  • Cyclooxygenase 1
  • DNA, Mitochondrial / genetics
  • Energy Metabolism*
  • Lipid Metabolism
  • Liver / metabolism
  • Membrane Proteins
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Oxidative Phosphorylation
  • Pyruvate Kinase / genetics*
  • Pyruvate Kinase / metabolism*

Substances

  • Amino Acids
  • DNA, Mitochondrial
  • Membrane Proteins
  • Cyclooxygenase 1
  • Ptgs1 protein, mouse
  • Pyruvate Kinase