The connection between tricarboxylic acid cycle enzyme mutations and pseudohypoxic signaling in pheochromocytoma and paraganglioma
Open accessAbstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.
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In animal models, fumarate hydratase inactivation induces a precancerous phenotype associated with chronic HIF pathway activation.
“In animal models, fumarate hydratase inactivation induces a precancerous phenotype associated with chronic HIF pathway activation, highlighting the intersection of mitochondrial metabolism, redox homeostasis, and HIF regulation [229,230].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [229]
The “FH and fumarate” section states that FH loss causes fumarate accumulation and that fumarate stabilizes HIFs, inducing a pseudohypoxic state in tumorigenesis. It does not report that FH inactivation induces a precancerous phenotype in animal models or establish chronic HIF activation in such models. The passages have no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDeficiencies in mitochondrial Krebs cycle enzymes SDH and FH promote accumulation of metabolites that inhibit PHDs, facilitating HIF-α accumulation.
“Beyond VHL disease, deficiencies in mitochondrial Krebs cycle enzymes, including succinate dehydrogenase and fumarate hydratase, promote accumulation of metabolites that inhibit PHDs, consequently facilitating HIF-α accumulation [228,229].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [229]
These metabolic perturbations result in pseudohypoxic signaling and increased cancer susceptibility.
“These metabolic perturbations, which are tightly linked to altered cellular redox balance, result in pseudohypoxic signaling and increased cancer susceptibility [229,230].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [229]
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Pseudohypoxic pheochromocytomas and paragangliomas dominate in children
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Self-citationTumour microenvironment in pheochromocytoma and paraganglioma
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TheVHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas
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- Authors
- Wang, Y., Liu, B., Li, F., Zhang, Y., Gao, X., Wang, Y., & Zhou, H.
- Affiliations
- First Hospital of Jilin University (CN)
- Jilin University (CN)
- Corresponding author
- Wang, Yishu
- Zhou, Honglan
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2023-10-05
- Volume
- 14
- Pages
- 1274239-1274239
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC10585109
- OpenAlex
- W4387374691
- Cited by
- 18
- References
- 113
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 6
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82270785)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- pheochromocytoma, paraganglioma, HIF-2α, succinate dehydrogenase, fumarate hydratase, isocitrate dehydrogenase, 2-hydroxyglutarate, tumor metabolic reprogramming, immunosuppressive tumor microenvironment, alpha-ketoglutarate-dependent dioxygenase, chromaffin cells
- MeSH terms
- Adrenal Gland Neoplasms, Citric Acid Cycle, Fumarates, Humans, Ketoglutaric Acids, Mutation, Paraganglioma, Pheochromocytoma, Succinates, Signal Transduction, Succinic Acid, Dioxygenases, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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