Abstract
Chronic social isolation (CSIS), a known risk factor for the development of major depressive disorders, is associated with hippocampal dysfunction. In rodent models, CSIS produces two phenotypes: CSIS-susceptible, which develop depressive- and anxiety-like behaviors, and CSIS-resilient, which maintain normal behavior despite stress. However, the biological mechanisms underlying resilience to stress remain elusive. Mitochondria, as central regulators of neuronal energy metabolism and redox balance, are potential mediators of stress susceptibility and resilience. This review summarizes comparative proteomic analyses of hippocampal nonsynaptic mitochondria (NSM) and synaptosome-enriched mitochondria from CSIS-susceptible and CSIS-resilient rats along with controls. In NSM of resilient rats relative to susceptible rats, remodeling enhanced energy production, limited reactive oxygen species, stabilized phosphate transport, and promoted removal of damaged components. Compared with controls, these changes optimized energy production, and selectively downregulated oxidative stress-promoting proteins. Conversely, synaptosome-enriched mitochondria from resilient rats showed downregulation of proteins related to synaptic energy metabolism and redox balance relative to CSIS-susceptible rats, but demonstrated upregulation of bioenergetic and antioxidant enzymes, molecular chaperones, and neuroprotective factors compared with controls. These proteomic signatures both highlight mitochondrial adaptability in promoting stress resilience and identify mitochondria as promising targets for the development of novel antidepressant therapies.