Succinate dehydrogenase germline mutation carriers: before tumours develop

Succinate dehydrogenase (SDH) is an enzyme complex that plays a major role in cellular metabolism, as it sits at the interface between carbon metabolism in the Krebs cycle and oxidative phosphorylation for energy production. The precursor and product of the enzymatic reaction, succinate and fumarate, respectively, are regulators of various cellular and biological processes such as epigenetic status, hypoxia responses and angiogenesis, metabolic reprogramming, tumorigenesis, and immune responses. Succinate is considered an oncometabolite, and SDHx genes are tumour suppressor genes. Carriers of germline pathogenic variants (PV) in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) carry a life-long risk of developing tumours, predominantly paragangliomas and phaeochromocytomas (PPGL). Research has focused mainly on the disease state in which, in accordance with the Knudson two-hit model, the second allele is inactivated in tumour cells; the biological consequences of which are massive intracellular accumulation of succinate and/or reactive oxygen species (ROS), which in turns leads to tumourigenesis. Little is known about the haplo-insufficient state, in which the wild-type SDHx copy at least partially sustains SDH function and keeps intracellular succinate and ROS levels in ranges that are, if not normal, then at least non-tumourigenic. This review will consolidate the literature regarding genotype differences between SDHx PV carriers, the phenotype of non-tumoral cells in healthy individuals, and the role of environmental factors in influencing tumour development, potentially via tipping succinate (or ROS) levels above a tumourigenic threshold.