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  2. Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery

Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery

  • J Med Chem. 2025 Feb 27;68(4):3970-3994. doi: 10.1021/acs.jmedchem.4c01779.
Panpan Yang 1 Wen Shuai 1 Xin Wang 1 Xiuying Hu 1 Min Zhao 1 Aoxue Wang 1 Yongya Wu 1 Liang Ouyang 1 Guan Wang 1
Affiliations

Affiliation

  • 1 Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
Abstract

Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient Mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting Mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several Mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for Other NDDs. Here, we describe the mechanism and key signaling pathway of Mitophagy and summarize the roles of defective Mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of Mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for Mitophagy mechanism exploration and drug design.

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