ATF5-mediated mitochondrial unfolded protein response protects against Pb-induced mitochondria damage in SH-SY5Y cell.

Mitochondria is the primary target of lead (Pb) in neural cells, and Pb exposure can cause impairment to mitochondrial function and morphology. Recent studies have reported that a conserved cellular stress response, called mitochondrial unfolded protein response (mtUPR), is activated in response to mitochondrial dysfunction and protein misfolding and play protective roles in aging and neurodegeneration, but it's unknown whether mtUPR could protect against Pb-induced neurotoxicity. In this study, we found that sublethal level exposure of PbAc (2.5 μM) could cause mitochondria damage and then activate mtUPR by promoting the expression of mitochondrial proteases (LonP1 and ClpP), molecular chaperone (HSPA1A). ATF5 mediated mtUPR activation as knocking out ATF5 significantly inhibited Pb-induced LonP1 and ClpP expression. Moreover, ATF5 deficiency exacerbated Pb-induced mitochondrial morphological and oxidative phosphorylation (OXPHOS) functional damage, resulting in oxidative stress and ultimately promoting cell death. Conversely, overexpression of ATF5 confers protection against Pb-induced oxidative stress and cell death. Collectively, thess results highlight that mtUPR mediated by ATF5 safeguards against mitochondria damage caused by Pb exposure, providing insights into the development of new strategies for mitigating the Pb neurotoxicity.