Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Blagosklonny, M. V. (2007). An anti-aging drug today: From senescence-promoting genes to anti-aging pill. Drug Discovery Today, 12, 218–224.

    Article  CAS  PubMed  Google Scholar 

  • Brandt, J., Bylsma, F. W., Gross, R., Stine, O. C., Ranen, N., & Ross, C. A. (1996). Trinucleotide repeat length and clinical progression in Huntington’s disease. Neurology, 46, 527–531.

    Article  CAS  PubMed  Google Scholar 

  • Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M., et al. (1997). Oxidative damage and metabolic dysfunction in Huntington’s disease: Selective vulnerability of the basal ganglia. Annals of Neurology, 41, 646–653.

    Article  CAS  PubMed  Google Scholar 

  • Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X. J., & Mattson, M. P. (2003). Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proceedings of the National Academy of Sciences of the United States of America, 100, 2911–2916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dulovic, M., Jovanovic, M., Xilouri, M., Stefanis, L., Harhaji-Trajkovic, L., Kravic-Stevovic, T., et al. (2014). The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiology of Disease, 63, 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Giacomello, M., Hudec, R., & Lopreiato, R. (2011). Huntington’s disease, calcium, and mitochondria. BioFactors, 37, 206–218.

    Article  CAS  PubMed  Google Scholar 

  • Heath-Engel, H. M., & Shore, G. C. (2006). Mitochondrial membrane dynamics, cristae remodelling and apoptosis. Biochimica et Biophysica Acta, 1763, 549–560.

    Article  CAS  PubMed  Google Scholar 

  • Ingram, D. K., Zhu, M., Mamczarz, J., Zou, S., Lane, M. A., Roth, G. S., & deCabo, R. (2006). Calorie restriction mimetics: An emerging research field. Aging Cell, 5, 97–108.

    Article  CAS  PubMed  Google Scholar 

  • Ishizuka, Y., Kakiya, N., Witters, L. A., Oshiro, N., Shirao, T., Nawa, H., & Takei, N. (2013). AMP-activated protein kinase counteracts brain-derived neurotrophic factor-induced mammalian target of rapamycin complex 1 signaling in neurons. Journal of Neurochemistry, 127, 66–77.

    CAS  PubMed  Google Scholar 

  • Jin, Y. N., Yu, Y. V., Gundemir, S., Jo, C., Cui, M., Tieu, K., & Johnson, G. V. (2013). Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One, 8, e57932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ju, T. C., Chen, H. M., Lin, J. T., Chang, C. P., Chang, W. C., Kang, J. J., et al. (2011). Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington’s disease. The Journal of Cell Biology, 194, 209–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, J., Moody, J. P., Edgerly, C. K., Bordiuk, O. L., Cormier, K., Smith, K., et al. (2010). Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Human Molecular Genetics, 19, 3919–3935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Labuzek, K., Suchy, D., Gabryel, B., Bielecka, A., Liber, S., & Okopien, B. (2010). Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacological Reports: PR, 62, 956–965.

    Article  CAS  PubMed  Google Scholar 

  • Lieberthal, W., Zhang, L., Patel, V. A., & Levine, J. S. (2011). AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation. American Journal of Physiology Renal Physiology, 301, F1177–F1192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, T. C., Buescher, J. L., Oatis, B., Funk, J. A., Nash, A. J., Carrier, R. L., & Hoyt, K. R. (2007). Metformin therapy in a transgenic mouse model of Huntington’s disease. Neuroscience Letters, 411, 98–103.

    Article  CAS  PubMed  Google Scholar 

  • MacDonald, M. E., Ambrose, C. M., Duyao, M. P., Myers, R. H., Lin, C., Srinidhi, L., et al. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s disease collaborative research group. Cell, 72, 971–983.

    Article  Google Scholar 

  • Mann, V. M., Cooper, J. M., Javoy-Agid, F., Agid, Y., Jenner, P., & Schapira, A. H. (1990). Mitochondrial function and parental sex effect in Huntington’s disease. Lancet, 336, 749.

    Article  CAS  PubMed  Google Scholar 

  • Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., et al. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4, 2192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Milakovic, T., & Johnson, G. V. (2005). Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. The Journal of Biological Chemistry, 280, 30773–30782.

    Article  CAS  PubMed  Google Scholar 

  • Pantovic, A., Krstic, A., Janjetovic, K., Kocic, J., Harhaji-Trajkovic, L., Bugarski, D., & Trajkovic, V. (2013). Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone, 52, 524–531.

    Article  CAS  PubMed  Google Scholar 

  • Ravn, P., Haugen, A. G., & Glintborg, D. (2013). Overweight in polycystic ovary syndrome. An update on evidence based advice on diet, exercise and metformin use for weight loss. Minerva Endocrinologica, 38, 59–76.

    CAS  PubMed  Google Scholar 

  • Reddy, P. H. (2014). Increased mitochondrial fission and neuronal dysfunction in Huntington’s disease: Implications for molecular inhibitors of excessive mitochondrial fission. Drug Discovery Today, 19, 951–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi, Y. (2001). A structural view of mitochondria-mediated apoptosis. Nature Structural Biology, 8, 394–401.

    Article  CAS  PubMed  Google Scholar 

  • Shirendeb, U. P., Calkins, M. J., Manczak, M., Anekonda, V., Dufour, B., McBride, J. L., et al. (2012). Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Human Molecular Genetics, 21, 406–420.

    Article  CAS  PubMed  Google Scholar 

  • Song, W., Chen, J., Petrilli, A., Liot, G., Klinglmayr, E., Zhou, Y., et al. (2011). Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nature Medicine, 17, 377–382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, J., Gallagher, D., DeVito, L. M., Cancino, G. I., Tsui, D., He, L., et al. (2012). Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell, 11, 23–35.

    Article  CAS  PubMed  Google Scholar 

  • Wang, H., Lim, P. J., Karbowski, M., & Monteiro, M. J. (2009). Effects of overexpression of Huntingtin proteins on mitochondrial integrity. Human Molecular Genetics, 18, 737–752.

    Article  CAS  PubMed  Google Scholar 

  • Yu, T., Fox, R. J., Burwell, L. S., & Yoon, Y. (2005). Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1. Journal of Cell Science, 118, 4141–4151.

    Article  CAS  PubMed  Google Scholar 

  • Zou, M. H., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W Gt, Schlattner, U., et al. (2004). Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. The Journal of Biological Chemistry, 279, 43940–43951.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge financial support from National Institute of Neurological Disorder and Stroke (NS082338 to WD), the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH Grants P30 CA006973 and UL1TR001079), and the Shared Instrument Grant (1S10RR026824-01) UL1TR001079 from National Center for Advancing Translational Sciences.

Author information

Authors and Affiliations

  1. 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

    Jing Jin, Hao Gu, Tianhua Ren, Mali Jiang, Michael Tao, Qi Peng & Wenzhen Duan

  2. Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Nicole M. Anders & Michelle A. Rudek

  3. Department of Emergency Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Tianhua Ren

  4. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michelle A. Rudek

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Wenzhen Duan

  6. Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Wenzhen Duan

Authors
  1. Jing Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole M. Anders
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tianhua Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mali Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qi Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michelle A. Rudek
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wenzhen Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wenzhen Duan.

Ethics declarations

Conflict of interest

All authors have declared the sources of research funding for this manuscript and have no financial or other contractual agreements that might cause (or be perceived as causes of) conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 514 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, J., Gu, H., Anders, N.M. et al. Metformin Protects Cells from Mutant Huntingtin Toxicity Through Activation of AMPK and Modulation of Mitochondrial Dynamics. Neuromol Med 18, 581–592 (2016). https://doi.org/10.1007/s12017-016-8412-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-016-8412-z

Keywords

Search

Navigation