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.

• MeSH
• Biosynthetic Pathways physiology   MeSH
• Energy Metabolism physiology   MeSH
• Stress, Physiological * MeSH
• Gene Knockout Techniques MeSH
• HEK293 Cells MeSH
• S Phase Cell Cycle Checkpoints physiology   MeSH
• Humans MeSH
• RNA, Small Interfering metabolism   MeSH
• Mitochondria metabolism   MeSH
• Mutation MeSH
• Mice, Inbred BALB C MeSH
• Mice, Nude MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Paraganglioma genetics   pathology   MeSH
• Electron Transport Complex II genetics   metabolism   MeSH
• Succinate Dehydrogenase genetics   metabolism   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Small Interfering MeSH
• Electron Transport Complex II MeSH
• respiratory complex II MeSH Browser
• SDHA protein, human MeSH Browser
• SDHB protein, human MeSH Browser
• Succinate Dehydrogenase MeSH

Mitochondrial complex II or succinate dehydrogenase (SDH) is at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. It has been shown that Sdh5 (SDHAF2/SDH5 in mammals) is required for flavination of the subunit Sdh1 (SDHA in human cells) in yeast. Here we demonstrate that in human breast cancer cells, SDHAF2/SDH5 is dispensable for SDHA flavination. In contrast to yeast, CRISPR-Cas9 nickase-mediated SDHAF2 KO breast cancer cells feature flavinated SDHA and retain fully assembled and functional complex II, as well as normal mitochondrial respiration. Our data show that SDHA flavination is independent of SDHAF2 in breast cancer cells, employing an alternative mechanism.

• Keywords
• SDH assembly factor, SDHA, SDHAF2, assembly factor, cancer biology, cancer cells, cell biology, complex II assembly, flavin adenine dinucleotide, flavination, flavinylation, mammal, mitochondria, mitochondrial complex II, mitochondrial respiratory chain complex, succinate dehydrogenase,
• MeSH
• Flavins MeSH
• Gene Knockdown Techniques MeSH
• Humans MeSH
• Mitochondrial Proteins genetics   metabolism   MeSH
• Mitochondria genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Breast Neoplasms genetics   metabolism   MeSH
• Protein Processing, Post-Translational * MeSH
• Electron Transport Complex II genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Flavins MeSH
• Mitochondrial Proteins MeSH
• Neoplasm Proteins MeSH
• Electron Transport Complex II MeSH
• SDHA protein, human MeSH Browser
• SDHAF2 protein, human MeSH Browser