I research altered mitochondrial quality control and metabolic dysregulation in neurodegenerative disease - Huntington's, Parkinson's and Alzheimer's diseases, and develop therapeutics for these diseases.
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Research Interests
Mitochondrial quality control and neurodegenerative diseases
Our research goals are to advance our knowledge on the fundamental mechanisms of mitochondrial-derived metabolic dysregulation and neurodegeneration. These intertwined biological processes exert a profound influence on human health. Our laboratory has been studying the molecular mechanisms governing these key biological processes and their complex interrelationship, by harnessing the power of functional proteomics and metabolomics combined with patient iPS cells and diseased animals. We also aim to develop “mitochondrial medicine” as therapeutic strategies for treating neurodegenerative diseases.
Mitochondria are critical organelles for cellular function through regulation of energy metabolism, ATP generation, and calcium handling. Dysfunctional mitochondria elicit the production of ROS and the deficits in metabolic activity, which ultimately affect numerous biological processes, including cellular bioenergetics, immune response, genomic stability and programmed cell death.
To attenuate these negative effects, mitochondria deploy several quality control pathways that are essential to maintain their pleiotropic functions and reduce mitochondrial stress. Mitochondrial quality control includes mitochondrial dynamics (fusion/fission), mitochondrial unfolded protein response (UPRmt) and mitochondria-related autophagy (mitophagy). These events are to repair damaged mitochondrial proteins, to facilitate mitochondrial adaption to the stress and to remove/degrade the irreversibly damaged mitochondria.
One of our research focuses is to understand the roles of mitochondrial dynamics-related proteins in mitochondrial and cellular functions, especially in the context of neurodegenerative diseases. Using a set of inhibitors targeting aberrant mitochondrial fission, we are determining whether manipulation of mitochondrial dynamics could provide a useful strategy for the treatment of neurodegenerative diseases. As another arc of research, we utilize unbiased proteomics to identify factors that participate in the regulation of UPRmt and mitophagy. We aim to understand how protein homeostasis of mitochondria controls cell life and influences neurodegeneration.
Publications
- Zhao Y, X Sun, D Hu, DA Prosdocimo, C Hoppel, MK Jain, R Ramachandran & X Qi. ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects. Nat Commun 10:1371, 2019.
- Hu D, X Sun, X Liao, X Zhang, S Zarabi, A Schimmer, Y Hong, C Ford, Y Luo & X Qi. Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta Neuropathol, 2019 Jun;137(6):939-960.
- Guo X, X Sun, D Hu, YJ Wang, H Fujioka, R Vyas, S Chakrapani, AU Joshi, Y Luo, D Mochly-Rosen & X Qi. VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease. Nature Commun 7:12646, 2016.
- Guo X, MH Disatnik, M Monbureau, M Shamloo, D Mochly-Rosen & X Qi. Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration. J. Clin. Invest. 123:5371-88, 2013.
- Su YC & X Qi, Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum. Mol. Genet. 22:4545-61, 2013.
- Luo F, K Herrup, X Qi* & Y Yang *. Inhibition of Drp1 hyper-activation is protective in animal models of experimental multiple sclerosis. Exp. Neurol. 292:21-34, 2017. (*, co-corresponding author)