Mitochondria are central to the metabolic circuitry that generates superoxide radicals/anions (O2•-) as a by-product of oxygen metabolism. By regulating superoxide levels, manganese superoxide dismutase plays important roles in numerous biochemical and molecular events essential for the survival of aerobic life. In this study, we used MitoParaquat (mPQ) to generate mitochondria-specific O2•- and stable isotope-resolved metabolomics tracing in primary human epidermal keratinocytes to investigate how O2•- generated in mitochondria regulates gene expression. The results reveal that isocitrate is blocked from conversion to α-ketoglutarate and that acetyl-coenzyme A (CoA) accumulates, which is consistent with a reduction in oxygen consumption rate and inactivation of isocitrate dehydrogenase (IDH) activity. Since acetyl-CoA is linked to histone acetylation and gene regulation, we determined the effect of mPQ on histone acetylation. The results demonstrate an increase in histone H3 acetylation at lysines 9 and 14. Suppression of IDH increased histone acetylation, providing a direct link between metabolism and epigenetic alterations. The activity of histone acetyltransferase p300 increased after mPQ treatment, which is consistent with histone acetylation. Importantly, mPQ selectively increased the nuclear levels and activity of the oxidative stress-sensitive nuclear factor erythroid 2-related factor 2. Together, the results establish a new paradigm that recognizes O2•- as an initiator of metabolic reprogramming that activates epigenetic regulation of gene transcription in response to mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)181-189
Number of pages9
JournalFree Radical Biology and Medicine
StatePublished - Feb 1 2022

Bibliographical note

Funding Information:
This work was supported by NIH grants R01 CA214638 and P20 GM121327 to Dr. Daret K. St. Clair and in part by NIH grant 1U24DK097215-01A1 to Teresa W. M. Fan. The authors would like to thank Mr. Michael Alstott for performing the OCR experiments using the Redox Metabolism Shared Resource Facilities funded by a Markey Cancer Center support grant ( P30 CA177558 ). Finally, we thank Professor Michael Murphy, Cambridge University, UK, for his generous gift of mPQ.

Publisher Copyright:
© 2021


  • Epigenetics
  • Metabolism
  • Mitochondria
  • Superoxide
  • TCA cycle
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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