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.