ReviewGenes2022
Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes.
Review in Genes, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- Genetic, cellular, and environmental factors influencing tumourigenesis in carriers of succinate dehydrogenase germline mutations.Endocrine-related cancer · 2026Review
- Antibacterial mechanisms of terpinen-4-ol against Aeromonas hydrophila.Archives of microbiology · 2026Article
- TheInternational journal of molecular sciences · 2025Article
- Succinate dehydrogenase-related pheochromocytoma and paraganglioma (SDHx-PPGL): clinical and genetic insights from an Indian study.Endocrine connections · 2025Article
- Chemoradiotherapy for recurrent CBTs case report.Discover oncology · 2025Article
- Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.Cancer & metabolism · 2024Article
- Paragangliomas of the Head and Neck: A Review of the Latest Diagnostic and Treatment Methods.Medicina (Kaunas, Lithuania) · 2024Review
- An evolving view of complex II-noncanonical complexes, megacomplexes, respiration, signaling, and beyond.The Journal of biological chemistry · 2023Review
- Mitochondrial Neurodegeneration: Lessons fromBiomolecules · 2023Review
- Succinate dehydrogenase variants in paraganglioma: why are B subunit variants 'bad'?Endocrine oncology (Bristol, England) · 2023Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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