Mitochondrial dysfunction in disease
Mitochondria are critical organelles for cellular function through regulation of energy metabolism, ATP generation, and calcium handling. A decline in mitochondrial activity has become a hallmark of a wide range of human diseases and ageing. My laboratory aims to understand how mitochondrial dysfunction contributes to neurodegeneration in diseases, such as Parkinson’s disease (PD) and Huntington’s disease (HD).
By combining general cultured cells, animal models and patient neurons differentiated from patient induced pluripotent stem cells (iPS cells), our research focuses include:
Identifying the role of mitochondrial dynamics in neurodegeneration
Mitochondria are highly dynamic organelles that constantly fuse and divide, forming either interconnected mitochondrial networks or separated fragmented mitochondria. These processes are believed to enable an effective adaptation of the mitochondrial compartment to the metabolic needs of the cell. We are studying the roles of mitochondrial dynamics-related proteins in mitochondrial and neuronal function under physiological and pathological conditions. Especially, by utilizing a set of fission peptide inhibitors which we recently developed, we are determining whether manipulation of mitochondrial dynamics could provide therapeutics for treatment of neurodegenerative diseases, such as PD and HD.
Understanding mitochondrial quality control in neurodegeneration
Mitochondrial quality control includes mitochondria-associated degradation, mitochondrial unfolded protein response and mitochondria-related autophagy (mitophagy). These events are to repair damaged mitochondrial proteins, to remove/degrade the irreversibly damaged mitochondria. Therefore, they are important processes to maintain normal mitochondrial functions. Using proteomics approach, we are identifying factors which participate in these events, and aim to understand how protein homeostasis of mitochondria controls neuronal life and contributes to disease pathogenesis of neurological disorders.
- Guo X, Sun XY, Di H, Wang YJ, Fujioka H, Vyas R, Chakrapani S, Joshi UA, Luo Y, Mochly-Rosen D and Qi X*, VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington’s disease. Nature Communications, in press
- Filichia E, Hoffer B, Qi X*, Luo Y*, Inhibition of Drp1 mitochondrial translocation provides neuronal protection in dopaminergic system in a Parkinson’s disease model induced by MPTP. Scientific Reports, in press (*, co-corresponding author)
- 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.
- Guo X, H Sesaki & X Qi*. Drp1 stabilizes p53 on the mitochondria to trigger necrosis under oxidative stress conditions in vitro and in vivo. Biochem. J. 461:137-46, 2014.