SDH loss truncates the TCA cycle at the succinate → fumarate step, forcing cells to generate lipid precursors via reductive carboxylation of glutamine: glutamate → α-KG → isocitrate → citrate (reverse TCA via IDH1/IDH2), which is exported to the cytoplasm and cleaved by ATP-citrate lyase (ACLY) to yield acetyl-CoA. Fatty acid synthase (FASN) then converts acetyl-CoA and malonyl-CoA into palmitate and longer-chain fatty acids required for membrane biogenesis, lipid signalling, and mitochondrial lipid supply. Independently, FASN products are required for mitochondrial fatty acid synthesis (mtFAS), which produces the lipoic acid moiety needed by key mitochondrial enzyme complexes. A FASN-SDHB synthetic interaction was directly demonstrated using the FASN inhibitor G28UCM in SDHB-knockout cell lines: G28UCM impaired FASN activity and mitochondrial fatty acid synthesis more profoundly in SDHB-deficient cells than in WT controls, establishing selective synthetic lethality (Rodríguez-Flores et al., Pharmacol Res 2026, PMID 41520938).

SDH loss constitutively upregulates FASN-dependent lipid synthesis (Rodríguez-Flores et al. Cancer Res 2026, PMID 41520938); FASN supplies mitochondrial fatty acid synthesis (mtFAS) with octanoyl-ACP, the obligate precursor for lipoic acid biosynthesis. Elevated lipoic acid synthesis increases the lipoylated pool of TCA cycle proteins (DLAT, DLST). Copper ionophores (elesclomol) deliver Cu²⁺ intracellularly; FDX1 (ferredoxin-1) reduces Cu²⁺ → Cu⁺, which directly attacks lipoylated TCA proteins, triggering proteotoxic aggregation and cell death via cuproptosis (Tsvetkov et al. Science 2022, PMID 35588000). SDH-deficient cells, with constitutively elevated lipoylated TCA proteins via the FASN→mtFAS→lipoic acid chain, may be selectively vulnerable to copper ionophore-induced cuproptosis.

Mitochondrial ferredoxin-1 (FDX1; UniProt Q14213) is an iron-sulfur [2Fe-2S] electron-transfer protein located in the mitochondrial inner membrane space. FDX1 serves as the proximal electron donor for adrenal steroidogenesis (CYP11A1, CYP11B1) and is required for Fe-S cluster biogenesis. Tsvetkov et al. (Science 2022, PMID 35588000) identified FDX1 as the essential mediator of copper ionophore-induced cuproptosis: FDX1 reduces Cu²⁺ → Cu⁺, and Cu⁺ directly attacks lipoylated TCA cycle proteins — principally DLAT (E2 subunit of pyruvate dehydrogenase) and DLST (E2 subunit of α-ketoglutarate dehydrogenase) — triggering their toxic aggregation and proteotoxic cell death. FDX1 knockdown confers cuproptosis resistance; FDX1 overexpression sensitizes cells. Relevance to SDH-deficient tumors: SDH loss drives FASN upregulation (Rodríguez-Flores et al. Cancer Res 2026, PMID 41520938), and FASN supplies mtFAS with octanoyl-ACP, the obligate lipoic acid precursor. Elevated lipoic acid biosynthesis in SDH-deficient mitochondria increases the lipoylated DLAT/DLST pool available for FDX1-mediated Cu⁺ attack, mechanistically predicting reduced cuproptosis threshold relative to SDH-intact cells. PPGL may be particularly relevant given high intrinsic FDX1 expression in adrenocortical/chromaffin-origin tissue (adrenal steroidogenesis). FDX1 is a predictive biomarker of cuproptosis sensitivity rather than a conventional pharmacological target; copper ionophores (elesclomol) are the drug class that engages FDX1 catalytic activity to generate cytotoxic Cu⁺.

UniProt: Q14213