Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease.

The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key organelles-mitochondria, lysosomes, and the endoplasmic reticulum (ER)-in AD, along with their physical and functional connectivity mechanisms. It emphasizes how their interaction network, formed through membrane contact sites, synergistically drives core AD pathological processes, including calcium signaling dysregulation, Aβ metabolism imbalance, mitochondrial quality control failure, lipid metabolism disorders, and neuroinflammation with apoptosis. This paper innovatively proposes that AD can be regarded as a "mitochondrial network disorder," the pathological essence of which lies in the systemic breakdown of communication between mitochondria. Building on this premise, we further discuss a therapeutic strategy centered on mitophagy enhancers to reshape the mitochondrial network and explore the translational medical prospects of achieving multi-target synergistic intervention by restoring the homeostasis of the mitochondrial network.