Autophagy aggravates multi-walled carbon nanotube-induced ferroptosis by suppressing PGC-1 dependent-mitochondrial biogenesis in lung epithelial cells

Abstract

Multi-walled carbon nanotube (MWCNT) induced respiratory toxicity has become a growing concern, with ferroptosis emerging as a novel mechanism implicated in various respiratory diseases. However, whether ferroptosis is involved in MWCNT-elicited lung injury and the underlying molecular mechanisms warrant further exploration. In this study, we found that MWCNT-induced ferroptosis is autophagy-dependent, contributing to its cellular toxicity. Inhibiting of autophagy by pharmacological inhibitors 3-MA or ATG5 gene knockdown significantly attenuated MWCNT-induced ferroptosis, concomitant with rescued mitochondrial biogenesis. Rapamycin, the autophagy agonist, exacerbated the mitochondrial damage and MWCNT-induced ferroptosis. Moreover, lentivirus-mediated overexpression of PGC-1α inhibited ferroptosis, while inhibition of PGC-1α aggravated ferroptosis. In summary, our study unveils ferroptosis as a novel mechanism underlying MWCNT-induced respiratory toxicity, with autophagy promoting MWCNT-induced ferroptosis by hindering PGC-1α-dependent mitochondrial biogenesis.