UQCRC1 downregulation impairs cognitive function in mice via AMPK inactivation

Background: Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an essential subunit of complex III in the mitochondrial respiratory chain. Although earlier studies have indicated that UQCRC1 downregulation causes cognitive impairment, the underlying mechanisms remain unclear.

Methods: To investigate its pathophysiological effects, we developed a mouse model with downregulated UQCRC1 expression. Hippocampus-dependent cognitive performance was evaluated using a series of behavioral paradigms. Mitochondrial bioenergetic status was assessed by measuring adenosine triphosphate (ATP) levels, while oxidative stress was quantified through detection of Reactive Oxygen Species (ROS). Molecular analyses were performed to assess AMP-activated protein kinase (AMPK) signaling dynamics and autophagic flux. Additionally, pharmacological interventions aimed at activating AMPK and enhancing lysosomal function were employed to elucidate mechanistic pathways.

Results: Downregulation of UQCRC1 resulted in significant deficits in hippocampus-dependent cognitive performance, accompanied by impaired mitochondrial bioenergetics (lower ATP synthesis) and elevated oxidative stress (increased ROS levels). Mechanistically, these phenotypes were associated with diminished AMPK activation and disrupted autophagic flux. Importantly, pharmacological activation of AMPK or enhancement of lysosomal activity in UQCRC1-deficient mice effectively ameliorated cognitive deficits and restored mitochondrial redox homeostasis .

Conclusions: This study identifies AMPK as a pivotal metabolic orchestrator of mitochondrial-lysosomal functional crosstalk and reveals its non-canonical function in maintaining neuronal homeostasis via coordinated regulation of autophagic flux and redox balance. Our findings propose AMPK-driven interorganelle communication as a modifiable therapeutic target for addressing cognitive decline resulting from mitochondrial dysfunction.

Autophagy; Cognition; Hippocampus; Mitochondria; ROS; Respiratory chain; UQCRC1.