NeuroMolecular Medicine

, Volume 18, Issue 4, pp 581–592 | Cite as

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

  • Jing Jin
  • Hao Gu
  • Nicole M. Anders
  • Tianhua Ren
  • Mali Jiang
  • Michael Tao
  • Qi Peng
  • Michelle A. Rudek
  • Wenzhen Duan
Original Paper
First Online:
Received:
Accepted:

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.

Keywords

Metformin Huntington’s disease Mitochondria AMPK 
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Notes

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.

Compliance with Ethical Standards

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.

Supplementary material

12017_2016_8412_MOESM1_ESM.docx (515 kb)
Supplementary material 1 (DOCX 514 kb)

References

  1. Blagosklonny, M. V. (2007). An anti-aging drug today: From senescence-promoting genes to anti-aging pill. Drug Discovery Today, 12, 218–224.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. Giacomello, M., Hudec, R., & Lopreiato, R. (2011). Huntington’s disease, calcium, and mitochondria. BioFactors, 37, 206–218.CrossRefPubMedGoogle Scholar
  7. Heath-Engel, H. M., & Shore, G. C. (2006). Mitochondrial membrane dynamics, cristae remodelling and apoptosis. Biochimica et Biophysica Acta, 1763, 549–560.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Shi, Y. (2001). A structural view of mitochondria-mediated apoptosis. Nature Structural Biology, 8, 394–401.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Jing Jin
    • 1
  • Hao Gu
    • 1
  • Nicole M. Anders
    • 2
  • Tianhua Ren
    • 1
    • 3
  • Mali Jiang
    • 1
  • Michael Tao
    • 1
  • Qi Peng
    • 1
  • Michelle A. Rudek
    • 2
    • 4
  • Wenzhen Duan
    • 1
    • 5
    • 6
  1. 1.Division of Neurobiology, Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Analytical Pharmacology Core, The Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Emergency Medicine, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
  4. 4.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Program in Cellular and Molecular MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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