Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.

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

Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.

Wang Y(1), An H(2), Liu T(3), Qin C(2), Sesaki H(4), Guo S(5), Radovick S(6), Hussain M(7), Maheshwari A(1), Wondisford FE(6), O’Rourke B(3), He L(8).

Author information: (1)Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (2)Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (3)Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (4)Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. (5)Department of Nutrition and Food Science, Texas A&M University, TX 77843, USA. (6)Departments of Pediatrics and Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. (7)Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA. (8)Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: heling@jhmi.edu.

Comment in Trends Endocrinol Metab. 2020 Apr;31(4):269-271. doi: 10.1016/j.tem.2020.02.003.

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.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.celrep.2019.09.070 PMCID: PMC6866677 PMID: 31693892 [Indexed for MEDLINE]

Conflict of interest statement: DECLARATION OF INTERESTS The authors declare no competing interests