Genetic impairment of succinate metabolism disrupts bioenergetic sensing in adrenal neuroendocrine cancer

Metabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of the mitochondrial tricarboxylic acid (TCA) cycle enzyme subunit succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss of SDHB induces the Warburg effect, triggers dysregulation of [Ca2+]i, and aberrantly activates calpain and protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a phospho-signaling cascade where GSK3 inhibition inactivates energy sensing by AMP kinase through dephosphorylation of the AMP kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC. A potent Cdk5 inhibitor, MRT3-007, reverses this phospho-cascade, invoking a senescence-like phenotype. This therapeutic approach halted tumor progression in vivo. Thus, we reveal an important mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers. [Display omitted] •Dysfunctional SDHB subunit causes aberrant activation of Cdk5 in pheochromocytoma (PC)•Aberrantly activated Cdk5 dysregulates a GSK3/PRKAG2/AMPKα signaling cascade•p25 overexpression in chromaffin cells and consequent aberrant Cdk5 activity causes PC•Cdk5 inhibition activates AMPK/p53 axis to rescue senescence and block PC progression Gupta et al. describe a signaling cascade by which TCA cycle deficiency inactivates bioenergetic sensing to cause adrenal gland cancer. Animal models and drugs targeting the cascade support the discovery, which suggests an additional explanation for Warburg’s description of cancers as uncontrolled cell proliferation despite metabolic impairment.