title: Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics.
abstract: 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.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Anders
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.|Department of Emergency Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Ren
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tao
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 8-121, Baltimore, MD, 21287, USA. wduan2@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wduan2@jhmi.edu.|Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. wduan2@jhmi.edu.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D000071058:Huntingtin Protein / Q000633:toxicity*; D006816:Huntington Disease / Q000188:drug therapy / Q000503:physiopathology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D000071058:Huntingtin Protein; D018696:Neuroprotective Agents; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Huntington’s disease; Metformin; Mitochondria