Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases

M itochondria act as the energetic hub of eukaryotic cells, orchestrating cellular energy metabolism via oxidative phosphorylation and the tricarboxylic acid (TCA) cycle, thereby subjecting them to continuous environmental stress. To address these challenges, mitochondria have developed a sophisticated array of quality-control mechanisms that provide adaptive resilience. These quality-control pathways encompassing mitochondrial biogenesis, dynamic remodeling, and mitophagy collectively safeguard cellular homeostasis. Among them, mitophagy plays a continuous role in surveying, identifying, and eliminating dysfunctional mitochondria, thereby preserving the integrity of the mitochondrial network and ensuring optimal bioenergetic function. When mitophagy is dysregulated, a cascade of protein homeostatic collapse and metabolic failure ensues, disrupting physiological cellular processes. Moreover, mitophagy plays a role in the development and progression of various pathologies, including neurodegenerative disorders, cardiovascular diseases, and cancer. In the context of neurodegeneration, aberrant mitophagy aggravates disease progression at the molecular, organellar, and cellular levels. Given that neuronal metabolism critically relies on oxidative phosphorylation, which primarily occurs within mitochondria, mitochondrial functional integrity directly determines neuronal energy supply and physiological capacity. Consequently, impaired mitophagy has been identified as a key determinant in the etiology of neurodegenerative diseases. This review systematically elucidates the key molecular mechanisms regulating mitophagy and how these mechanisms contribute to the onset and progression of neurodegenerative diseases. It also summarizes potential therapeutic agents targeting mitophagy to improve neurodegenerative disorders.