N, N-dimethylformamide exposure induced liver abnormal mitophagy by targeting miR-92a-1-5p-BNIP3L pathway in vivo and vitro

N, N-dimethylformamide (DMF) isa widely existing harmful environmental pollutant from industrial emission which can threat human health for both occupational and general populations. Epidemiological and experimental studies have indicated liver as the primary target organ of DMF. However, the molecular mechanism under DMF-induced hepatoxicity remains unclear. In the present study, we identified that DMF could induce abnormal autophagy flux in cells. We also showed that DMF-induced mitochondrial dysfunction and lethal mitophagy which further leads to au-tophagic cell death. Next, miRNA microarray analysis identified miR-92a-1-5p as the most down-regulated miRNA upon DMF exposure. Mechanistically, miR-92a-1-5p regulated mitochondrial function and mitophagy by targeting mi-tochondrial protein BNIP3L. Exogenous miR-92a-1-5p significantly attenuated DMF-induced mitochondrial dysfunc-tion and mitophagy in vitro and in vivo. Our study highlights the mechanistic link between miRNAs and mitophagy under environmental stress, which provided a new clue for the mitochondrial epigenetics mechanism on environmen-tal toxicant-induced hepatoxicity.

Automated summary

In this study, we found that DMF could induce abnormal autophagy flux and lethal mitophagy in cells, resulting in autophagic cell death. miR-92a-1-5p was identified as the most down-regulated miRNA upon DMF exposure and it regulated mitochondrial function and mitophagy by targeting mitochondrial protein BNIP3L. Exogenous miR-92a-1-5p significantly attenuated DMF-induced mitochondrial dysfunction and mitophagy both in vitro and in vivo.