Controlled power: how biology manages succinate-driven energy release

Abstract

Oxidation of succinate by mitochondria can generate a higher protonmotive force (pmf) than can oxidation of NADH-linked substrates. Fundamentally, this is because of differences in redox potentials and gearing. Biology adds kinetic constraints that tune the oxidation of NADH and succinate to ensure that the resulting mitochondrial pmf is suitable for meeting cellular needs without triggering pathology. Tuning within an optimal range is used, for example, to shift ATP consumption between different consumers. Conditions that overcome these constraints and allow succinate oxidation to drive pmf too high can cause pathological generation of reactive oxygen species. We discuss the thermodynamic properties that allow succinate oxidation to drive pmf higher than NADH oxidation, and discuss the evidence for kinetic tuning of ATP production and for pathologies resulting from substantial succinate oxidation in vivo.

Site IQ in mitochondrial complex I generates S1QEL-sensitive superoxide/hydrogen peroxide in both the reverse and forward reactions

“…The requirement here is to set up conditions with FET or RET but favouring superoxide/hydrogen peroxide production at site I Q , i.e. with high QH 2 /Q ratio, high protonmotive force and high ΔpH (which are usually absent from FET assays with G + M alone [ 18 , 32 ]), and then to show under the specific conditions of the assay whether electron flow is from added G + M to NADH to Q (forward electron transport) or from added succinate or G3P to QH 2 to NAD + (reverse electron transport). To determine the direction of electron flow we employ a rotenone challenge.…”

“…Is the same true of mitochondria in intact cells? From theoretical considerations we expect FET to be the default in cells, generating ATP from the oxidation of NADH using all three mitochondrial proton-pumping complexes, I, III and IV [32,40], whereas FET using only complexes III and IV to drive ATP synthesis while electrons flow in RET from QH 2 to NAD is expected to occur only under unusual or contrived conditions, such as the transient oxidation of excess succinate during ischaemia-reperfusion [27,28]. There is an expectation of FET in bulk cell cultures and tissues, as these generally respond to rotenone challenge by a reduction of their matrix NAD(P) pool [41][42][43][44].…”

Succinate metabolism in the retinal pigment epithelium uncouples respiration from ATP synthesis

“…Succinate oxidation can stimulate a high Δρ ( Mookerjee et al, 2021 ). There is an exponential relationship between Δρ and H + leak ( Nicholls, 1974 , 1997 ).…”

Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells

“…Which of these sites run in isolated mitochondria is completely dependent on the experimental conditions, in particular which substrates are presented to the mitochondria [ 7 – 15 ]. The nature of the substrate determines not only which mitochondrial redox centers become reduced and hence able to pass their electrons directly to oxygen, but also the magnitude of the protonmotive force [ 16 ], which can modulate the reactivity of these reduced centers. In particular, the rate of superoxide and/or hydrogen peroxide formation at the flavin site of complex I of the electron transport chain, site I F , is determined by the matrix NAD pool size and reduction state [ 17 , 18 ].…”