1. Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints.
- Author
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Bezawork-Geleta A, Wen H, Dong L, Yan B, Vider J, Boukalova S, Krobova L, Vanova K, Zobalova R, Sobol M, Hozak P, Novais SM, Caisova V, Abaffy P, Naraine R, Pang Y, Zaw T, Zhang P, Sindelka R, Kubista M, Zuryn S, Molloy MP, Berridge MV, Pacak K, Rohlena J, Park S, and Neuzil J
- Subjects
- Animals, Biosynthetic Pathways physiology, Cell Line, Tumor, Electron Transport Complex II genetics, Gene Knockout Techniques, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Mutation, Paraganglioma genetics, RNA, Small Interfering metabolism, S Phase Cell Cycle Checkpoints physiology, Succinate Dehydrogenase genetics, Succinate Dehydrogenase metabolism, Xenograft Model Antitumor Assays, Electron Transport Complex II metabolism, Energy Metabolism physiology, Mitochondria metabolism, Paraganglioma pathology, Stress, Physiological
- Abstract
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 CII
low , 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.- Published
- 2018
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