Mitochondrial Complex II Function and Dysregulation in Cancer Biology

Mitochondrial Complex II, also known as succinate dehydrogenase (SDH), occupies a unique position at the intersection of the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain (ETC). By catalysing the oxidation of succinate to fumarate and funneling electrons into the ETC via ubiquinone, Complex II contributes both to cellular ATP synthesis and to the maintenance of redox balance. In cancer biology, loss or mutation of SDH subunits precipitates succinate accumulation, stabilising hypoxia‐inducible factors and driving pseudo‐hypoxic gene programmes that promote angiogenesis, proliferation and metabolic reprogramming. Furthermore, aberrant Complex II activity can modulate reactive oxygen species (ROS) production, eliciting DNA damage or adaptive survival pathways. Recent evidence indicates that alternative assemblies of Complex II serve as metabolic checkpoints under energy stress, linking bioenergetic state to cell‐cycle progression. Dysregulation of Complex II therefore not only underpins tumour initiation and progression through oncometabolite signalling but also creates exploitable vulnerabilities for targeted therapies aimed at restoring metabolic homeostasis or selectively inducing cancer cell death.

Research from Nature Portfolio

Recent studies have revealed that the flavination state of the SDHA subunit critically influences both the optical and metabolic signatures of oral squamous cell carcinoma (OSCC). Reduced levels of flavinated SDHA in tumour cells, as compared with adjacent normal tissue, account for altered autofluorescence and accompany diminished SDHB stability, collectively reprogramming mitochondrial respiration and unveiling diagnostic and therapeutic targets. In parallel, foundational work has characterised an alternative assembly of Complex II, termed CIIlow, which emerges under bioenergetic stress to restrain DNA synthesis and enforce cell‐cycle checkpoints. Loss of CIIlow leads to unchecked nucleotide biosynthesis and bypass of S-phase arrest, whereas patient samples harbouring SDH mutations corroborate its homeostatic role. Together, these insights position Complex II not merely as a metabolic enzyme but as a dynamic regulator of nutrient sensing and proliferative control in cancer cells.

Mitochondrial Complex II Function and Dysregulation in Cancer Biology publication trend

The graph below shows the total number of articles in mitochondrial complex ii function and dysregulation in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Succinate dehydrogenase (SDH/Complex II): A four-subunit enzyme that oxidises succinate to fumarate in the TCA cycle and transfers electrons to ubiquinone in the ETC.

Flavination: The covalent attachment of flavin adenine dinucleotide (FAD) to the SDHA subunit, essential for its catalytic activity.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can act as signalling molecules or mediators of oxidative damage.

Oncometabolite: A metabolite, such as succinate, whose accumulation drives tumourigenic signalling pathways.

Ubiquinone (coenzyme Q): A lipid‐soluble electron carrier in the ETC that accepts electrons from Complex II and transfers them to Complex III.

References

1. Flavinated SDHA underlies the change in intrinsic optical properties of oral cancers. Communications Biology (2023).
2. Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints. Nature Communications (2018).
3. Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme. Biomedicines (2024).
4. Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad. Biomedicines (2022).
5. Comprehensive overview of how to fade into succinate dehydrogenase dysregulation in cancer cells by naringenin-loaded chitosan nanoparticles. Genes & Nutrition (2024).
6. Mitochondrial complex II and reactive oxygen species in disease and therapy. Redox Report (2020).