Mitophagy deficiency and calcium dyshomeostasis underlying the pathogenesis and progression of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder defined by three pathological hallmarks: amyloid-β (Aβ) deposition, tau hyperphosphorylation leading to neurofibrillary tangles formation, and neuronal loss. Mounting evidence over the past decade has underscored that mitophagy deficiency and calcium dyshomeostasis play pivotal regulatory roles in AD pathological progression, with these two abnormalities persisting throughout the entire course of disease onset and development. Mitophagy impairment can result in the accumulation of dysfunctional mitochondria, thereby further exacerbating calcium dyshomeostasis which can suppress autophagic flux in turn. This reciprocal interaction establishes a vicious cycle that can synergistically accelerate Aβ plaque and neurofibrillary tangle formation, impair synaptic structure and function, and ultimately elicit neuronal programmed cell death and cognitive decline. This review systematically summarizes the biological basis of mitophagy and calcium homeostasis, as well as their mutual regulatory networks. It places particular emphasis on deciphering the pathological mechanisms through which concurrent impairments of these two pathways synergistically drive AD pathogenesis and progression. Furthermore, we propose intervention strategies targeting to modulate mitophagy deficiency and calcium dyshomeostasis, which hold great promise for providing novel insights and potential therapeutic targets for the clinical management of AD.