Despite two decades of
paraganglioma-
pheochromocytoma research, the fundamental question of how the different
succinate dehydrogenase (SDH)-related
tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of
reactive oxygen species (ROS) but ROS are inhibited by rising
succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in
oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of
succinate dehydrogenase to
fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified
succinate threshold model of
tumor initiation. Truncating SDH variants cause high
succinate accumulation and likely initiate
tumorigenesis via disruption of 2-oxoglutarate-dependent
enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower
succinate accumulation and thus initiate
tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of
succinate.