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Editorial
. 2018 Sep 24;6(1):35.
doi: 10.1186/s40635-018-0202-5.

Succinate and the shortcut to the cure of metformin-induced lactic acidosis

Alessandro Protti  1
Affiliations
Editorial

Succinate and the shortcut to the cure of metformin-induced lactic acidosis

Alessandro Protti. Intensive Care Med Exp. .

Abstract

Inhibition of the respiratory chain complex I plays a key role in the pathogenesis of metformin-induced lactic acidosis. In a work recently published in this journal, a novel cell-permeable succinate prodrug (NV118) increased in vitro mitochondrial oxygen consumption coupled with energy production and decreased lactate production in intact human platelets intoxicated with metformin. This result was interpreted in light of a "bypass" strategy. NV118 entered platelets and released succinate in their cytoplasm; succinate in turn donated electrons to complex II and thus reactivated the flow of electrons to the distal part of the respiratory chain independent of complex I. Herein, I will (1) comment on these findings; (2) highlight the potential therapeutic application of succinate in other critical conditions accompanied by complex I inhibition, including sepsis, traumatic brain injury, and inherited neurological disorders; and (3) examine the most important issues that remain to be solved to transfer these observations to the bedside.

Keywords: Hypoxia; Intoxication; Lactic acidosis; Metformin; Mitochondria; Sepsis; Succinate; Traumatic brain injury.

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The author declares that he has no competing interests.

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Figures

Fig. 1
Fig. 1
Succinate ameliorates mitochondrial oxygen use and energy production when complex I is inhibited, as during metformin intoxication Respiratory electron transfer and phosphorylation of ADP to produce ATP are indirectly coupled through the proton-motive force that is generated by the activity of the electron transport chain [8]. At toxic dose, metformin somehow inhibits complex I; the flow of electrons through the respiratory chain and related mitochondrial oxygen use, proton-motive force, and energy production accordingly decrease. Succinate delivered into the cell is oxidized to fumarate (as part of the Krebs cycle) by the succinate dehydrogenase, a subunit of the respiratory chain complex II. This reaction is coupled with the direct transfer of electrons to ubiquinone (Q) and to the more distal part of the respiratory chain, independent of complex I. Thanks to this “bypass” strategy, succinate improves mitochondrial respiration, coupled proton extrusion, and energy production during metformin intoxication.
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