Guanqin Ma1,2 · Erlin Wang4  · Xiaoxu Yan4  · Xiang‑Xiong Xu1,2 · Xiaohong Li6  · Xueling Ma5  · Wan‑Hua Yang4  · Jianxiong Zeng1,2,4 · Xiaochun Xie3

1 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China 

2 Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650201, China 

3 Interdisciplinary Eye Research Institute (EYE‑X Institute), Bengbu Medical University, Bengbu 233030, China 

4 Department of Geriatrics, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China 

5 Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150081, China 

6 College of Life Sciences, Yunnan University, Kunming 650201, China

Abstract

Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia—the brain-resident immune cells—initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS−STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS–STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.

Keywords

Mitochondrial dysregulation; Microglia; Neuroinflammaging; Neurodegeneration; cGAS–STING

[SpringerLink]