The crosstalk between mitochondrial dysfunction and endoplasmic reticulum stress promoted ATF4‐mediated mitophagy induced by hexavalent chromium

Abstract

Chromium (Cr) compounds are markedly toxic and carcinogenic. Previously, we found that Cr (VI) induced autophagy in A549 cells. Here, the effect of mitochondrial dysfunction and endoplasmic reticulum (ER) stress on inducing mitophagy was investigated in both A549 and H1299 cells. Exposure to Cr (VI) for 6 h significantly enhanced reactive oxygen species (ROS) production and reduced mitochondrial membrane potential (MMP). Transmission electron microscopy showed that Cr (VI) induced mitochondrial morphological changes, such as, mitochondrial swelling and vacuolization. The elevated expression of GRP78 and p-PERK suggested that Cr (VI) resulted in ER stress. Both mitochondrial dysfunction and ER stress played an important role in Cr (VI)-induced mitophagy, as the mitochondrial function inhibitor, carbonyl cyanide 3-chlorophenylhydrazone (CCCP) induced PINK1 and PARK2 and increased the expression of GRP78 and p-PERK while the levels of Cr (VI)-induced PINK1, PARK2, LC3-II were reduced after ER stress inhibitor, phenylbutyric acid (4PBA) pretreatment. When A549 cells were treated with CCCP and 4-PBA simultaneously, CCCP-induced expressions of PINK1, PARK2 and LC3-II decreased significantly compared with that of only CCCP-treated cells, indicating that there was a crosstalk between mitochondria and ER in inducing mitophagy. Additionally, the crosstalk between mitochondrial dysfunction and ER stress modulated the expression of Cr (VI)-induced ATF4, which resulted in mitophagy. Collectively, our data demonstrated that Cr (VI)-induced mitophagy mediated by ATF4 via the crosstalk between ER stress and mitochondrial dysfunction.

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.…”

“…ER stress has been known to induce impairment of mitochondrial dynamics and mitophagy in metabolic disturbances, and activation of pro‐apoptotic signals 22 . Several environmental stressors have also been known 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.…”

“…Much evidence has been lately gathered regarding the interplay of ER stress and mitophagy responses in the externally induced stress responses in the cells. Chromium, an environmental toxicant and carcinogen, has been demonstrated to induce ATF‐4‐mediated mitophagy in A549 cells via ROS upregulation and mitochondrial depolarization 10 . Similarly, another environmental toxicant, lead (PB2+), has recently been demonstrated to induce mitophagy via ER stress pathway in HEK293 cells 11 .…”

“…Chromium, an environmental toxicant and carcinogen, has been demonstrated to induce ATF-4-mediated mitophagy in A549 cells via ROS upregulation and mitochondrial depolarization. 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.…”

Knockdown of Y-box binding protein 1 induces autophagy in early porcine embryos

“…Mitochondrial fission and fusion maintain the mitochondrial morphology, homeostasis, and inheritance via mitochondrial biogenesis and mitophagy ( Ma et al, 2020 ). Mitophagy is crucial for mitochondrial quality control ( Dlamini et al, 2021 ). Dysfunctional mitochondria can generate apoptotic signals to induce cell death ( Zhang, 2013 ).…”