Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints

Nat Commun. 2018 Jun 7;9(1):2221. doi: 10.1038/s41467-018-04603-z.


Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CIIlow, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CIIlow is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosynthetic Pathways / physiology
  • Cell Line, Tumor
  • Electron Transport Complex II / genetics
  • Electron Transport Complex II / metabolism*
  • Energy Metabolism / physiology*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / metabolism*
  • Mutation
  • Paraganglioma / genetics
  • Paraganglioma / pathology*
  • RNA, Small Interfering / metabolism
  • S Phase Cell Cycle Checkpoints / physiology
  • Stress, Physiological*
  • Succinate Dehydrogenase / genetics
  • Succinate Dehydrogenase / metabolism
  • Xenograft Model Antitumor Assays


  • RNA, Small Interfering
  • respiratory complex II
  • Electron Transport Complex II
  • SDHA protein, human
  • SDHB protein, human
  • Succinate Dehydrogenase