Research Article Open Access
Volume 1 | Issue 2 | DOI: https://doi.org/10.33696/pathology.1.009

Succinate Accumulation Links Mitochondrial MnSOD Depletion to Aberrant Nuclear DNA Methylation and Altered Cell Fate

  • 1Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa 52242, USA
  • 2Department of Surgery, The University of Iowa, Iowa City, Iowa 52242, USA
  • 3Department of Pathology, The University of Iowa, Iowa City, Iowa 52242, USA
  • 4Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242, USA
  • #These authors contributed equally
+ Affiliations - Affiliations

Corresponding Author

Frederick E. Domann, frederick-domann@uiowa.edu

Received Date: August 27, 2020

Accepted Date: December 09, 2020


Previous studies showed that human cell line HEK293 lacking mitochondrial superoxide dismutase (MnSOD) exhibited decreased succinate dehydrogenase (SDH) activity, and mice lacking MnSOD displayed significant reductions in SDH and aconitase activities. Since MnSOD has significant effects on SDH activity, and succinate is a key regulator of TET enzymes needed for proper differentiation, we hypothesized that SOD2 loss would lead to succinate accumulation, inhibition of TET activity, and impaired erythroid precursor differentiation. To test this hypothesis, we genetically disrupted the SOD2 gene using the CRISPR/Cas9 genetic strategy in a human erythroleukemia cell line (HEL 92.1.7) capable of induced differentiation toward an erythroid phenotype. Cells obtained in this manner displayed significant inhibition of SDH activity and ~10-fold increases in cellular succinate levels compared to their parent cell controls. Furthermore, SOD2-/- cells exhibited significantly reduced TET enzyme activity concomitant with decreases in genomic 5-hmC and corresponding increases in 5-mC. Finally, when stimulated with δ-aminolevulonic acid (δ-ALA), SOD2-/- - HEL cells failed to properly differentiate toward an erythroid phenotype, likely due to failure to complete the necessary global DNA demethylation program required for erythroid maturation. Together, our findings support the model of an SDH/succinate/TET axis and a role for succinate as a retrograde signaling molecule of mitochondrial origin that significantly perturbs nuclear epigenetic reprogramming and introduce MnSOD as a governor of the SDH/succinate/TET axis.


Mitochondria, Superoxide dismutase, Iron homeostasis, Succinate dehydrogenase, Retrograde signaling, DNA methylation, Epigenetic control, Gene expression

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