Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria

Biochem J. 2014 Sep 15;462(3):475-87. doi: 10.1042/BJ20140620.


The biguanide metformin is widely prescribed for Type II diabetes and has anti-neoplastic activity in laboratory models. Despite evidence that inhibition of mitochondrial respiratory complex I by metformin is the primary cause of its cell-lineage-specific actions and therapeutic effects, the molecular interaction(s) between metformin and complex I remain uncharacterized. In the present paper, we describe the effects of five pharmacologically relevant biguanides on oxidative phosphorylation in mammalian mitochondria. We report that biguanides inhibit complex I by inhibiting ubiquinone reduction (but not competitively) and, independently, stimulate reactive oxygen species production by the complex I flavin. Biguanides also inhibit mitochondrial ATP synthase, and two of them inhibit only ATP hydrolysis, not synthesis. Thus we identify biguanides as a new class of complex I and ATP synthase inhibitor. By comparing biguanide effects on isolated complex I and cultured cells, we distinguish three anti-diabetic and potentially anti-neoplastic biguanides (metformin, buformin and phenformin) from two anti-malarial biguanides (cycloguanil and proguanil): the former are accumulated into mammalian mitochondria and affect oxidative phosphorylation, whereas the latter are excluded so act only on the parasite. Our mechanistic and pharmacokinetic insights are relevant to understanding and developing the role of biguanides in new and existing therapeutic applications, including cancer, diabetes and malaria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology
  • Antineoplastic Agents / pharmacology
  • Biguanides / pharmacology*
  • Biguanides / therapeutic use
  • Cattle
  • Diabetes Mellitus, Type 2 / drug therapy
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / drug effects*
  • Hep G2 Cells
  • Humans
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Liver / drug effects*
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Oxidative Phosphorylation / drug effects*
  • Plasmodium / drug effects
  • Proguanil / pharmacology
  • Rats
  • Reperfusion Injury / prevention & control
  • Triazines / pharmacology


  • Antimalarials
  • Antineoplastic Agents
  • Biguanides
  • Triazines
  • cycloguanil
  • Metformin
  • Mitochondrial Proton-Translocating ATPases
  • Electron Transport Complex I
  • Proguanil