Abstract

Lonp1 is the main mitochondrial matrix protease responsible for maintaining mitochondrial proteostasis through the degradation of damaged or misfolded proteins. Although impaired Lonp1 expression or activity has been linked to mitochondrial dysfunction and oxidative stress in peripheral tissues and non-neuronal cells, its role in the brain, and particularly in hippocampal function, remains unexplored. Here, we provide the first in vivo evidence that Lonp1 activity is a critical regulator of mitochondrial redox homeostasis, synaptic integrity, and learning in the hippocampus. We administered the Lonp1 inhibitor Sesamin intranasally to 4-month-old adult Senescent-Acelerated Mouse Prone 8 (SAMP8) mice for 6 weeks. Subsequently, we conducted cognitive tests to assess hippocampal-dependent learning and memory. We also examined Lonp1 proteolytic activity using the FITC-Casein assay, performed Golgi staining to evaluate dendritic spines, and used fluorescent and luminescent probes to investigate mitochondrial function. Interestingly, we selectively impaired Lonp1 function at an early stage of age-related brain vulnerability. Lonp1 inhibition led to the accumulation of mitochondrial Lonp1 substrates and a marked reduction in mitochondrial bioenergetic capacity, as reflected by decreased ATP production and a robust increase in mitochondrial reactive oxygen species (ROS). These redox alterations were accompanied by selective synaptic remodeling, characterized by a reduction in thin dendritic spines without changes in total spine density, and by impaired hippocampus-dependent learning, while memory retention remained preserved. Thus, our findings identify Lonp1 as a previously unrecognized regulator of mitochondrial redox balance and synaptic structure in the hippocampus. Importantly, Lonp1 inhibition recapitulates key features of brain aging, linking defective mitochondrial proteostasis to ROS-driven synaptic vulnerability and cognitive dysfunction. This study establishes Lonp1-dependent mitochondrial quality control as a central node connecting redox dysregulation to synaptic failure and highlights Lonp1 as a novel target for strategies aimed at preserving mitochondrial and cognitive function during aging.