Focusing on microglial mitochondria-lysosome crosstalk and neuroinflammation underlying depression: from molecular pathways to potential therapeutic interventions

TL;DR

This paper reviews how microglial mitochondria-lysosome interactions contribute to neuroinflammation in depression and explores potential new treatments.

Contribution

The paper introduces microglial mitochondria-lysosome crosstalk as a novel mechanistic hub in depression-related neuroinflammation.

Findings

Disrupted mitochondrial-lysosome contact sites in microglia lead to increased ROS and pro-inflammatory cytokines.

Abnormalities in microglial mitochondria-lysosome crosstalk reinforce neuroinflammatory circuits in depression.

Restoring microglial mitochondria-lysosome pathways is proposed as a new therapeutic strategy for depression.

Abstract

Depression is a prevalent emotional disorder that significantly impacts global health. Its etiology is multifactorial, and current therapeutic options have notable limitations, underscoring the need to identify novel molecular targets and therapeutic strategies. Neuroinflammation is a key pathophysiological feature of depression, with microglia serving as innate immune cells in the central nervous system (CNS), playing a crucial role in neuroinflammation sensing and amplification. Mitochondria and lysosomes, which are responsible for energy metabolism and waste degradation, respectively, forms non-fusogenic interactions at mitochondrial–lysosomal contact sites (MLCs) in microglia, promoting physical contact and signal transduction, thereby modulating microglial metabolic states and inflammatory phenotypes. Disruption of MLCs can lead to reactive oxygen species (ROS) accumulation, enhanced pro-inflammatory cytokine production, and amplification of neuroinflammatory cascades, thereby accelerating the neuroinflammation-driven pathogenesis of depression. In this review, we focus on how microglial MLCs drive neuroinflammation and contribute to the pathophysiology of depression. First, this review explores how peripheral immune dysregulation, oxidative stress, and impaired autophagy initiate and sustain neuroinflammatory responses that exacerbate depressive behaviors. Then, this review elucidates how mitochondrial dysfunction and lysosomal pathology amplify inflammatory signaling and promote the progression of depressive neurobiology. It highlights microglial MLCs abnormalities as a crucial mechanistic hub, detailing how disrupted Ca²+ crosstalk, impaired autophagic flux, and redox imbalance reinforce depression-related neuroinflammatory circuits. Finally, it summarizes emerging therapeutic strategies aimed at restoring microglial MLCs-regulated pathways and proposes future research directions to facilitate the development of neuroinflammation-targeted antidepressant therapies.

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