Development of enhancers of mitochondrial function as therapeutic candidates for neurodegenerative diseases
To advance the translational impact of targeting mitochondrial dysfunction in neurological disorders, our research team has utilized the rational design of peptide regulators and high-throughput screening (HTS) to identify therapeutic approaches that enhance mitochondrial function and promote cell survival in models of neurodegenerative diseases. The identification of these mitochondrial enhancers thus paves the way for the development of 'mitochondrial medicine,' with the potential to treat neurodegenerative diseases and other conditions characterized by mitochondrial deficits.
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Hu D, Sun XY, Shang YT, Lundberg K, Adams D* and Qi X*., A small-molecule stabilizer of the Calpastatin-Calpain-2 complex restores mitochondrial function and mitigates Neurodegeneration. Science Advances, 2026 Mar 27;12(13):eaeb1174. PMID: 41894510.
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Hu D, Sun XY and Qi X*, Disrupting α-Synuclein–ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson’s disease models. Molecular Neurodegeneration, 2025 Dec 22;20(1):126. PMID: 41430713
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Choi W#, Fattah M#, Shang YT#, Thompson MP, Carrow K, Hu D, Liu ZR, Avram M, Bailey K, Berger O, Qi X* and Gianneschi NC*, Mutant Huntingtin Mimetic Protein-like Polymer Blocks Mitochondrial damage, Rescues Huntington’s Neurons, and Slows Onset of Neuropathology In Vivo. #, co-first author. *, co-corresponding author. Science Advances, 2024, Nov 1, 10, eado8307. PMID: 39485846
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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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Hu D, Sun SY, Magpusao A, Fedorov Y, Thompson M, Wang BL, Lundberg K, Adams D and Qi X, Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease. Nature Communications, 2021 Sep 6;12(1):5305. PMID: 34489447
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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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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, 2016 Aug 26;7:12646. PMID: 27561680
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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