Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics

Neuromolecular Med. 2016 Dec;18(4):581-592. doi: 10.1007/s12017-016-8412-z. Epub 2016 May 25.


Huntington's disease (HD) is a devastating neurodegenerative disease caused by the pathological elongation of the CAG repeats in the huntingtin gene. Caloric restriction (CR) has been the most reproducible environmental intervention to improve health and prolong life span. We have demonstrated that CR delayed onset and slowed disease progression in a mouse model of HD. Metformin, an antidiabetic drug, mimics CR by acting on cell metabolism at multiple levels. Long-term administration of metformin improved health and life span in mice. In this study, we showed that metformin rescued cells from mutant huntingtin (HTT)-induced toxicity, as indicated by reduced lactate dehydrogenase (LDH) release from cells and preserved ATP levels in cells expressing mutant HTT. Further mechanistic study indicated that metformin activated AMP-activated protein kinase (AMPK) and that inhibition of AMPK activation reduced its protective effects on mutant HTT toxicity, suggesting that AMPK mediates the protection of metformin in HD cells. Furthermore, metformin treatment prevented mitochondrial membrane depolarization and excess fission and modulated the disturbed mitochondrial dynamics in HD cells. We confirmed that metformin crossed the blood-brain barrier after oral administration and activated AMPK in the mouse brain. Our results urge further evaluation of the clinical potential for use of metformin in HD treatment.

Keywords: AMPK; Huntington’s disease; Metformin; Mitochondria.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Huntingtin Protein / toxicity*
  • Huntington Disease / drug therapy
  • Huntington Disease / physiopathology
  • Metformin / pharmacology*
  • Mice
  • Mitochondria / drug effects
  • Mitochondrial Dynamics / drug effects*
  • Neuroprotective Agents / pharmacology


  • Huntingtin Protein
  • Neuroprotective Agents
  • Metformin
  • AMP-Activated Protein Kinases