BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

Abstract

Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.

The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure

“…Specifically, we tested the SH-SY5Y cells with 0.1, 0.5, 1 and 5 μM of cortisol for 6, 12, 24 and 48 h, to mimic acute and chronic stressors ( Choi et al, 2021 ; Silva et al, 2019 ). As reported in Supplementary Figure 1 , regardless of the cortisol concentrations herein used, Rack1 gene and protein expression were not altered at the earliest time points (6 and 12 h) while we observed a decrease of Rack1 mRNA and protein levels at 24 and 48 h with 1 and 5 μM of cortisol.…”

Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

“…However, during experimentation, subjects were placed individually in filled glass cylinder for a period of 6 min and the total duration of immobility was measured (ANY-maze, Stoelting Co.) as indicative of depressive-like behaviour. Immobility was defined as floating or remaining motionless without leaning against the wall of the cylinder [33].…”

Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

“…A recent study reported that NIX (but not BNIP3) is downregulated by stress-induced glucocorticoids, contributing to chronic stress-induced synaptic defects, which has been shown on mouse hippocampal neurons and human neuroblastoma SH-SY5Y cells. This decreased NIX expression is achieved through the binding of the glucocorticoid receptor to PGC-1α, which leads to its downregulation and decreased nuclear translocation, thus decreasing NIX-dependent mitophagy [ 57 ]. Figure 2 presents the scheme of receptor-mediated mitophagy.…”