CUMS stress facilitates hippocampal neural mitophagy through FIS1/MFF-mediated mitochondrial fragmentation

The chronic unpredictable mild stress (CUMS) paradigm influences the neuronal count in the dentate gyrus (DG) region of the hippocampus, potentially linking to mitophagy induced by mitochondrial fragmentation. Fission mitochondrial 1 (FIS1)/mitochondrial fission factor (MFF) represents one of the mechanisms regulating mitochondrial fission and autophagy. Herein, we investigated the effects of CUMS on mitophagy and mitochondrial fragmentation in hippocampal DG neurons, along with their modulation of the mitochondrial fission pathway governed by FIS1/MFF. Our results demonstrated that CUMS stress augmented mitophagy in hippocampal DG neurons. Concurrently, it exacerbated the tendency toward mitochondrial fragmentation. The impact on the upstream regulatory pathway of mitochondrial fragmentation manifested as upregulation of FIS1 and downregulation of MFF, resulting in a net loss of mitochondrial content and a subsequent energy deficit. These findings suggest that CUMS stress, by modulating the FIS1/MFF balance, increases mitophagy stemming from mitochondrial fragmentation in hippocampal DG neurons.NEW & NOTEWORTHY We show that chronic unpredictable mild stress disrupts mitochondrial homeostasis in hippocampal neurons by simultaneously promoting mitophagy via a FIS1/MFF imbalance and suppressing biogenesis via PGC1α downregulation. This dual impairment leads to a cellular energy deficit, providing a novel link between stress, mitochondrial dysfunction, and the pathophysiology of depression.