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Succinate ameliorates mitochondrial oxygen consumption of metformin-intoxicated human platelets

Introduction

Metformin intoxication inhibits mitochondrial complex I and oxygen consumption (VO2). Succinate bypasses complex I by donating electrons to complex II. The aim of this study was to clarify whether succinate ameliorates mitochondrial VO2 of metformin-intoxicated human platelets.

Methods

Platelet-rich-plasma was incubated for 72 hours with metformin at a final concentration of 0 mg/l (control), 1.66 mg/l (therapeutic dose) or 166 mg/l (toxic dose). Platelet VO2 was then measured with a Clark-type electrode, in the presence of glutamate plus malate (complex I electron donors) (final concentration: 20 mmol/l for both) or succinate (complex II electron donor) (30 mmol/l), before and after adding cyanide (40 mmol/l). Mitochondrial (cyanide-sensitive) and extra-mitochondrial (cyanide-insensitive) VO2 were corrected for platelet count.

Results

The main results, from four preliminary experiments, are shown in Figure 1. In the presence of glutamate plus malate, only platelets incubated with a high dose of metformin had a mitochondrial VO2 significantly lower than controls. In the presence of succinate, mitochondrial VO2 of controls did not change significantly whereas that of platelets incubated with metformin did. The effect of succinate tended to become larger as the dose of metformin was increased from 0 up to 166 mg/l (0.3 ± 0.2 vs. 0.6 ± 0.3 vs. 1.0 ± 0.3 nmol/minute*106 cells) (P = 0.068).Even so, mitochondrial VO2 of platelets incubated with.the highest dose of metformin did not return to the levels of controls. Extra-mitochondrial VO2 was always the same.

Figure 1
figure1

Mitochondrial oxygen use of human platelets incubated with metformin.

Conclusion

Succinate ameliorates (but does not return to normal) mitochondrial VO2 of human platelets incubated with a toxic dose of metformin.

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Correspondence to A Protti.

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Protti, A., Monti, M., Lecchi, A. et al. Succinate ameliorates mitochondrial oxygen consumption of metformin-intoxicated human platelets. Crit Care 17, P451 (2013). https://doi.org/10.1186/cc12389

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Keywords

  • Oxygen
  • Public Health
  • Glutamate
  • Final Concentration
  • Cyanide