Targeting mitochondrial quality control in Alzheimer’s disease: Mechanisms and therapeutic potential of phytomedicines

Alzheimer's disease (AD) is a neurodegenerative disorder driven partly by mitochondrial dysfunction, notably the failure of mitochondrial quality control (MQC). Phytochemicals have emerged as multi-target agents capable of restoring MQC, offering a promising therapeutic avenue. This review outlines how dysregulated MQC contributes to AD pathogenesis and summarizes the current evidence on phytochemicals that target key MQC processes—including mitochondrial dynamics, biogenesis, mitophagy, oxidative stress, and apoptosis—to exert neuroprotection. In AD, MQC is broadly impaired, characterized by suppressed biogenesis, excessive mitochondrial fission, defective mitophagy, oxidative stress, and calcium dyshomeostasis. Phytochemicals counter these defects through diverse mechanisms: restoring fission-fusion balance, enhancing biogenesis and mitophagic clearance, attenuating oxidative stress via Nrf2 activation, and inhibiting mitochondria-dependent apoptosis by modulating Bcl-2 family proteins and caspases. Despite these promising preclinical findings, several challenges remain, including poor bioavailability, limited blood-brain barrier penetration, lack of standardized preparations, and insufficient clinical validation. This review provides a mechanistic rationale for targeting MQC in AD and highlights future directions for translating phytochemical-based strategies into effective therapies. • This review systematically elucidates the comprehensive dysfunction of the mitochondrial quality control system and its core pathogenic role in Alzheimer's disease. • It comprehensively summarizes preclinical evidence that phytochemicals exert neuroprotective effects by multi-target modulation of various MQC components. • The article identifies the key translational challenges—including bioavailability, long-term safety, and clinical validation—and outlines future research directions.