Compartment-Specific Mitochondrial Proteomic Alterations in Rat Hippocampus Following Chronic Social Isolation Stress

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria (NSM) and synaptosomal fractions containing synaptic mitochondria from adult male rats exposed to six weeks of CSIS, an animal model of depression, compared to controls. The compartment-specific proteomic alterations reveal mechanisms underlying mitochondrial dysregulation, providing molecular insights into the depression-like phenotype. Hippocampal NSM exhibit changes in energy metabolism-related proteins, including components of the tricarboxylic acid cycle and oxidative phosphorylation, as well as mitochondrial transport proteins and alterations in chaperones, structural and translational proteins, and monoamine oxidase, further elucidating how these proteomic changes contribute to mitochondrial dysregulation. In contrast, synaptosomal proteomics reveal predominantly increased protein abundance associated with energy metabolism, signaling, cytoskeletal organization, protein quality control, and vesicle trafficking, suggesting compensatory adaptations. Together, these findings highlight compartment-specific mitochondrial proteomic changes that may underlie depression-like behaviors and represent potential targets for therapeutic intervention.