Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel

Abstract

Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.

Fig. 1 ∣. Mitochondrial bioenergetics and the coenzyme Q (CoQ) pool.

a, An overview of the bioenergetic parameters that control CoQ/CoQH₂ redox state. Aggregate electron supply from many sources in the cell dictate the rate of electron supply to CoQ. Rate of CoQH₂ oxidation dictates the rate of electron loss from CoQH₂. Rate of CoQH₂ oxidation depends on cellular ATP demand, which is indirectly sensed via the Δp, as well as oxygen tension. αGP, α-glycerophosphate; αGPDH, α-glycerophosphate dehydrogenase; DHD, dihydroorotate dehydrogenase; ETF, electron transferring flavoprotein; SQR, sulfide:quinone oxidoreductase. Image created with BioRender.com. b, Summary of the effects of electron supply imbalance into and from the mitochondrial CoQ pool on mitochondrial succinate. Elevated aggregate supply and/or decreased demand are sufficient to drive selective accumulation of succinate via the ΔG = 0 reaction mediated by SDH. AAs, amino acids.

Fig. 2 ∣. Succinate controls mitochondrial superoxide production through mitochondrial complex I.

Accumulated succinate exerts redox pressure on the mitochondrial CoQ pool. Under conditions of elevated Δp (low cellular ATP demand) and normoxia, redox pressure on the CoQ pool poises electrons onto the terminal flavin of complex I to facilitate single-electron reduction of oxygen to generate superoxide. Mitochondrial superoxide is rapidly dismutated to hydrogen peroxide, which acts as a metabolic signal through reversible covalent modification of protein cysteine residues.

Fig. 3 ∣. Accumulated mitochondrial succinate regulates cellular α-KG-dependent dioxygenases.

The substrate of the α-KG-dependent dioxygenase (αKGDD) reaction becomes hydroxylated in a reaction utilizing three co-substrates: divalent iron (Fe²⁺), α-KG and molecular oxygen (O₂). During catalysis, α-KG becomes decarboxylated to succinate and CO₂. Accumulated succinate inhibits this reaction.

Fig. 4 ∣. pH-gated succinate secretion regulates systemic physiology.

Succinate accumulation within mitochondria is equilibrated and trapped within the cell. However, under conditions of cellular acidification, achieved under states of high glycolytic flux or hypoxia, a proportion of the succinate pool is transformed into a monocarboxylate, which renders it amenable to secretion through MCT1. Upon pH-gated secretion, succinate exerts a broad range of context- and cell-type-specific paracrine and endocrine responses via its cognate G-protein coupled receptor SUCNR1.

Fig. 5 ∣. Logic of succinate as a local and systemic bioenergetic sensor.

Summary of how succinate integrates bioenergetic parameters of oxygen tension, substrate supply, ATP utilization and intracellular pH, to elicit highly context-dependent local and systemic adaptation.