The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells

Abstract

It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.

Rosmarinic acid alleviates ultraviolet‐mediated skin aging via attenuation of mitochondrial and ER stress responses

“…to induce ER stress-mediated mitophagy. 10,11 However, the role of mitochondrial specific autophagy (mitophagy) has not yet been explored in UV-B irradiated dermal fibroblasts. Moreover, the effect of UV-B-induced ER stress on mitochondrial dynamics and mitophagy still needs to be elucidated.…”

“…10 Similarly, another environmental toxicant, lead (PB2+), has recently been demonstrated to induce mitophagy via ER stress pathway in HEK293 cells. 11 Thus, our current study aims to identify the effect of physiological UV-B dose on mitophagy in human dermal fibroblasts and whether UV-B-induced ER stress contributes to mitophagy.…”

Electrical Stimulation Attenuates Disuse Muscular Atrophy by Modulating Endoplasmic Reticulum Stress-induced Parkin-dependent Mitophagy

“…Studies to date have shown that endoplasmic reticulum stress can regulate mitophagy in other areas [39,40,41]. Gao K et al [39] reported that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.…”

Associations between exposure to single cadmium, lead, mercury and mixtures and women’s infertility and long-term amenorrhea

“…Pb, Cd, and Hg have been shown to exhibit similar toxic mechanisms by inducing oxidative stress and endoplasmic reticulum (ER) stress, 42,43 which compromises the reduction-oxidation hemostasis and eventually results in adverse health outcomes. [44][45][46] ER stress has also been revealed as a key molecular mechanism in various female reproductive functions and disorders, such as ovarian injury via ER stress-mediated apoptosis/autophagy, regulation of gestational length by the uterine ER stress, oocyte maturation, and embryo implantation. [47][48][49][50] In the federal Tox21 program, the ER Stress Response Element β-lactamase reporter gene assay (ESRE-bla) is used to screen potential toxicants, including heavy metals.…”