NDUFB9 ameliorates CUMS-induced depression-like behavior by promoting mitophagy

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Major depressive disorder (MDD) is linked to mitochondrial dysfunction, but underlying mechanisms remain unclear.
• Transcriptomic analysis identified TFAM, SURF1, and NDUFB9 as key genes in MDD patients' peripheral blood.
• Single-cell analysis revealed these genes, particularly NDUFB9, are expressed in prefrontal cortex inhibitory neurons.

Purpose of the Study:

• To investigate the role of TFAM, SURF1, and NDUFB9 in MDD.
• To explore the therapeutic potential of NDUFB9 in alleviating depression-like behaviors.
• To elucidate the mechanism by which NDUFB9 impacts mitochondrial function and neuronal survival.

Main Methods:

• Transcriptomic analysis of MDD patients' blood and prefrontal cortex (PFC).
• Establishment of a chronic unpredictable mild stress (CUMS) mouse model to mimic MDD.
• Overexpression of NDUFB9 in CUMS mice, alongside assays for mitophagy, mitochondrial function, and neuronal death.

Main Results:

• CUMS exposure induced depressive behaviors and mitochondrial dysfunction in mice, with decreased TFAM, SURF1, and NDUFB9 expression in the PFC.
• NDUFB9 overexpression significantly reduced depressive behaviors, restored mitochondrial function, and decreased inhibitory neuron death in CUMS mice.
• NDUFB9 enhanced mitophagy via the PINK1/Parkin pathway by stabilizing PINK1, crucial for NDUFB9-mediated recovery.

Conclusions:

• NDUFB9 plays a critical role in alleviating depression-like behavior by enhancing mitophagy.
• NDUFB9 stabilizes PINK1, promoting mitophagy and protecting inhibitory neurons.
• Targeting NDUFB9 represents a promising therapeutic strategy for major depressive disorder (MDD).