Fluoxetine reprograms hippocampal mitochondrial subcellular proteomes in chronically socially isolated rats

Abstract Brain mitochondrial dysfunction may play a crucial role in the mechanisms of major depressive disorders, impairing neuronal bioenergetics and synaptic transmission. While the antidepressant fluoxetine (Flx) is primarily known for modulating serotonin levels, it may also enhance mitochondrial function in stress-affected brain regions, particularly the hippocampus. This review summarizes findings from proteomic analyses of hippocampal nonsynaptic mitochondria (NSM) and synaptosomal mitochondria from adult male rats subjected to six weeks of chronic social isolation (CSIS), an animal model of depression, followed by Flx treatment lasting three weeks of six-week CSIS, compared to CSIS. In NSM of CSIS rats, Flx upregulates proteins involved in pyruvate metabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and ATP synthesis, suggesting an overall enhancement of mitochondrial energy production. Additional upregulation encompasses one-carbon folate metabolism, mitochondrial transport, structural organization, and proteostasis. Within synaptosomal mitochondria, Flx induces a distinct yet complementary proteomic signature, upregulating selects TCA cycle enzymes and catalytic OXPHOS components, remodeling the respiratory chain to support enhanced bioenergetic capacity. Flx further upregulates proteins mediating ketone body and amino acid catabolism, antioxidant defense system and protein quality control mechanisms. Notably, monoamine oxidase-A exhibits consistent upregulation across both mitochondrial subpopulations, likely representing a compensatory response to maintain monoamine homeostasis. These findings suggest that Flx mediates part of its antidepressant effects through subcellular compartment-specific reprogramming of the mitochondrial proteome, underscoring mitochondria as one of the modulators of depression-related molecular alterations and potential therapeutic targets.