Defining a causal role of mitochondrial dynamics impairment in the pathogenesis of neurological disorders
Mitochondria are highly dynamic organelles that continuously divide and fuse within cells. Mitochondrial fission and fusion—collectively referred to as mitochondrial dynamics—affect mitochondrial morphology, biogenesis, distribution within cells, and cell death. We are currently investigating the molecular mechanisms by which excessive mitochondrial fission leads to neuronal degeneration in Huntington's, Parkinson's, and Alzheimer's diseases. We pioneered the use of the peptide inhibitor P110, which selectively inhibits the hyper-activation of the primary fission protein, Drp1. Findings from multiple groups, including our own, have shown that inhibition of Drp1-mediated excessive mitochondrial fission with P110 treatment corrects mitochondrial damage and reduces disease-associated pathology in vitro and in vivo. These findings provide direct evidence of a causal role for impaired mitochondrial fission in the pathogenesis of human diseases. Therefore, the development of inhibitors targeting excessive mitochondrial fission holds the potential to open new therapeutic avenues for the treatment of neurological disorders and other diseases where mitochondrial dysfunction is a factor.
Additionally, we have recently employed unbiased proteomics to profile Drp1 downstream effectors in neurons and glial cells across various neurodegenerative disease models. We are further investigating these candidate proteins, including ATAD3A, to elucidate the detailed mechanisms by which impaired mitochondrial dynamics contribute to mitochondrial genome instability, mitochondria-derived neuroinflammation, and neurodegeneration.
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Sridharan PS, Miller E, Kee T, Chakraborty S, Hu D, Tripathi SJ, Koh Yeojung, Chaubey K, Dhar M, Vazquez-Rosa E, Shin MK, Alvarado RA, Barker S, Franke K, Cintron-Perez CJ, Flanagan M, Castellani RJ, Gefen T, Wilson BM, Fujioka H, Woo JA, Kang D, Paul BD, Qi X* and Pieper AA*, Early transient inhibition of excessive mitochondrial fission after brain injury blocks transition to chronic neurodegenerative disease. *, co-corresponding author. Cell Reports Medicine, 2024 Sep 17;5(9):101715, PMID: 39241772
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Zhao YY, Hu D, Wang RH, Sun XY, Ropelewski P, Hubler Z, Lundberg K, Wang QQ, Adams D, Xu R and Qi X, ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models by impairing brain cholesterol turnover. Nature Communications, 2022 Mar 2;13(1):1121. PMID: 35236834
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Zhang XW, Wang RH, Hu D, Sun XY, Fujioka H, Lundberg K, Chan ER, Wang QQ, Xu R, Flanagan ME, Pieper AA, and Qi X, Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease. Science Advances. 2020 Dec 4;6(49):eabb8680. PMID: 33277246
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Zhao YY, Sun XY, Hu D, Prosdoci D, Jain M, Hoppel C, Ramachandran R, Qi X, ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation with bioenergetics defects. Nature Communications, 2019 Mar 26;10(1):1371. PMID: 30914652
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Su YC and Qi X*. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. 2013 Nov 15;22(22): 4545-61. PMID: 23813973
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Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D and Qi X, Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. J Clin Invest., 2013 Dec;123(12):5371-88. PMID: 24231356