title: Metformin directly acts on mitochondria to alter cellular bioenergetics.
abstract: BACKGROUND
  Metformin is widely used in the treatment of diabetes, and there is interest in 'repurposing' the drug for cancer prevention or treatment. However, the mechanism underlying the metabolic effects of metformin remains poorly understood.
  
  
  METHODS
  We performed respirometry and stable isotope tracer analyses on cells and isolated mitochondria to investigate the impact of metformin on mitochondrial functions.
  
  
  RESULTS
  We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival.
  
  
  CONCLUSIONS
  Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, QC H3A 1A3, Canada ; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Andrzejewski
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, QC H3A 1A3, Canada ; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, 3755 Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada ; Cancer Prevention Center, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada ; Department of Oncology, McGill University, 546 Pine Ave. W., Montréal, QC H2W 1S6, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, QC H3A 1A3, Canada ; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
keywords: Cancer; Citric acid cycle; Complex I; Metabolism; Metformin; Mitochondria; Respiration