Mitochondrial quality control in neurodegenerative diseases
Our laboratory focuses on understanding the roles of mitochondrial quality control in neurodegenerative diseases including Parkinson’s and Huntington’s disease. We use the combination of unbiased proteomics and genomics, cellular and molecular biology, genetic manipulation in vitro and in vivo, patient iPS cells-derived cell culture and diseased animals to investigate the fundamental mechanisms and pathways by which mitochondrial impairment contributes to neurodegeneration. We also utilize rationally designed peptide inhibitors of protein-protein interactions and high throughput screening approach 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 energy supply, 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 useful strategy for 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.
Mitochondrial quality control under stressed conditions
Mitochondrial quality control pathways under stress or diseased conditions. Accumulation of misfolded proteins within mitochondria induces the mitochondrial unfolded protein response (UPRmt), leading to the transcriptional upregulation of mitochondrial chaperones and proteases. Mitochondrial stress can cause alterations in mitochondrial dynamics. An increase in Drp1-mediated fission of mitochondria leads to mitochondrial fragmentation and subsequent mitochondrial damage. Fragmented and damaged mitochondria can be eliminated by mitochondria-associated autophagy, termed mitophagy. VCP-mediated mitophagy pathway is implicated in the pathogenesis of neurodegenerative diseases. These processes are interconnected in response to stress and diseased damage.
- 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. Nat Commun 7:12646, 2016.
- Filichia E, B Hoffer, X Qi* & Y Luo*. Inhibition of Drp1 mitochondrial translocation provides neural protection in dopaminergic system in a Parkinson's disease model induced by MPTP. Sci Rep 6:32656, 2016. (*, Co-corresponding authors)
- 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.
- X Qi*, Qvit N, Su YC & Mochly-Rosen D. A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J. Cell. Sci. 126:789-802, 2013. (*, Corresponding author)
- 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.