Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK

Cell Rep. 2019 Nov 5;29(6):1511-1523.e5. doi: 10.1016/j.celrep.2019.09.070.


Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.

Keywords: AMPK; Drp1; adenine nucleotides; diabetes; insulin resistance; membrane potential; metformin; mitochondrial respiration/fission.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Adenine Nucleotides / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Cell Respiration / drug effects
  • Cell Respiration / genetics
  • Diet, High-Fat
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism
  • Gene Knockout Techniques
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / ultrastructure
  • Hyperglycemia / drug therapy
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism
  • Liver / physiopathology
  • Liver / ultrastructure
  • Metformin / analysis
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / genetics
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / ultrastructure
  • Mitochondrial Dynamics / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*


  • Adenine Nucleotides
  • Blood Glucose
  • Hypoglycemic Agents
  • Metformin
  • Protein Kinases
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Electron Transport Complex I