One deficiency, different outcomes: Succinate dehydrogenase loss in chromaffin cell vs. fibroblast models of paraganglioma

Heterozygosity for loss‐of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional Sdhx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. Here we characterize two available murine SDH-loss cell lines, one representing PPGL-susceptible chromaffin cells and the other PPGL-resistant fibroblasts. Consistent with previous analyses, we find strikingly different effects of SDH loss in these two cellular contexts, including evidence of residual Complex I activity only in SDH-loss immortalized mouse chromaffin cells. This work supports the hypothesis that chromaffin cells may uniquely tolerate SDH loss and sets the stage for analyses of unique vulnerabilities in SDH-loss chromaffin cells.