Spirulina and Succinate Signalling: SDH, HIF-1alpha Stabilisation, and Immunometabolism

Succinate Accumulation in Macrophage Immunometabolism

LPS-stimulated macrophages undergo a profound metabolic reprogramming: the TCA cycle is broken at two points creating an accumulation of succinate and citrate. Succinate accumulates because succinate dehydrogenase (SDH/Complex II, SDHA/B/C/D) runs in reverse under ROS-rich conditions (succinylation of SDHB, Complex I-derived electrons reducing fumarate to succinate), and because glutamine-derived alpha-KG is converted to succinate via the truncated reverse TCA pathway. The second break at isocitrate dehydrogenase leads to citrate accumulation (ACLY substrate). These two breaks create the characteristic LPS-induced TCA pattern termed the "broken TCA cycle."

Succinate-PHD2 Inhibition and HIF-1alpha

Prolyl hydroxylases PHD1/2/3 (EGLN1/2/3) require alpha-ketoglutarate (alpha-KG) and O2 as co-substrates to hydroxylate HIF-1alpha Pro402/Pro564. Succinate (and fumarate, oxaloacetate) competitively inhibits PHDs by occupying the alpha-KG binding site, preventing HIF-1alpha hydroxylation and VHL-mediated proteasomal degradation. Thus, LPS-driven succinate accumulation stabilises HIF-1alpha under normoxic inflammatory conditions (pseudohypoxia), driving: (1) HIF-1alpha-NF-kB co-activation of IL-1beta (HRE in IL-1beta promoter); (2) VEGF for macrophage-driven angiogenesis at wounds; (3) iNOS and LDHA for glycolytic/NO-mediated bactericidal function.

SUCNR1 (GPR91): Extracellular Succinate Receptor

Succinate released from activated cells binds SUCNR1 (GPR91) on dendritic cells and macrophages, activating Gq/Gi to promote DC chemotaxis, IL-1beta production, and mast cell priming. SUCNR1 signalling amplifies the inflammatory alarm signal (succinate as a danger-associated metabolite, DAME). Ischaemia-reperfusion releases massive succinate from mitochondria (oxidised by SDH during reperfusion, generating O2 radical via reverse electron transport through Complex I). Spirulina's Nrf2 activation reduces the ROS driving SDH reverse electron transport and attenuates NF-kB-driven LPS-induced TCA reprogramming.

Itaconate: Endogenous Counter-Regulator

Itaconate (from immune-responsive gene 1/IRG1/ACOD1 converting cis-aconitate to itaconate in macrophage TCA) is an endogenous SDH inhibitor: itaconate covalently modifies SDHB Cys90 (succinylation-like mechanism) and competitively inhibits SDH, reducing succinate accumulation and HIF-1alpha stabilisation. Itaconate also directly alkylates Keap1 Cys151/Cys273/Cys288 (similar to PCB), activating Nrf2 and inducing ATF3, HO-1, and HMOX1, creating an endogenous anti-inflammatory counter-loop. Itaconate derivative 4-octyl itaconate (4-OI) is being explored therapeutically. Spirulina's PCB is mechanistically analogous to itaconate in Keap1 modification.

Alpha-KG and TET Enzyme Epigenetics

Alpha-ketoglutarate (alpha-KG) is not only a PHD co-substrate but also the co-factor for TET1/2/3 DNA demethylases (5mC → 5hmC → 5fC → 5caC) and JMJD histone demethylases (H3K27me3 demethylation). LPS-induced TCA reprogramming that reduces alpha-KG relative to succinate (succinate/alpha-KG ratio elevation) suppresses TET activity, leading to DNA hypermethylation at inflammatory gene loci. This is relevant to spirulina's epigenetic effects: Nrf2-driven restoration of TCA function (via SIRT3 Complex I/II activation) restores alpha-KG levels, supporting TET-mediated demethylation and the anti-inflammatory epigenetic state.

SDH and Phaeochromocytoma

Germline mutations in SDH subunit genes (SDHB, SDHC, SDHD, SDHAF2) predispose to phaeochromocytoma, paraganglioma, GIST, and renal cell carcinoma. SDH-mutant tumours accumulate succinate massively, creating global DNA hypermethylation (G-CIMP phenotype, TET inhibition) and pseudohypoxia (HIF-1alpha stabilisation). This oncometabolite (succinate) drives the epigenetic and transcriptomic changes. While spirulina has no therapeutic role in SDH-mutant hereditary syndromes, understanding the succinate signalling axis explains how spirulina's TCA normalisation and Nrf2-TET support are relevant to non-hereditary inflammatory pseudohypoxia contexts.