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Arsenic induces ferroptosis and acute lung injury through mtROS-mediated mitochondria-associated endoplasmic
Meng-Die Li1, Lin Fu1, Bian-Bian Lv1
1Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Department of Toxicology, Anhui Medical University, Hefei 230032, China.
Abstract:
The goal of this study was to analyze whether mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction mediated arsenic (As)-evoked pulmonary ferroptosis and acute lung injury (ALI). As exposure led to alveolar structure damage, inflammatory cell infiltration and pulmonary function decline in mice. Ferritin, the marker of iron overload, was increased, GPX4, the index of lipid peroxidation, was decreased in As-exposed lungs and pulmonary epithelial cells (MLE-12). Pretreatment with ferrostatin-1 (Fer-1), the inhibitor of ferroptosis, alleviated As-evoked ALI. In addition, As-induced non-heme iron deposition was inhibited in Fer-1 pretreated-mice. Moreover, As-triggered mitochondria damage and ferroptosis were mitigated in Fer-1 pretreated-MLE-12 cells. Mechanistically, PERK phosphorylation and mitofusin-2 (Mfn-2) reduction was observed in As-exposed MLE-12 cells and mice lungs. Additionally, the interaction between PERK and Mfn-2 was downregulated and MAMs dysfunction was observed in As-exposed MLE-12 cells. Intriguingly, PERK inhibitor and Mfn-2-overexpression all mitigated As-induced ferroptosis in MLE-12 cells. Additionally, CLPP and mtHSP70, the markers of mitochondrial stress, were upregulated, mitochondrial ROS (mtROS) was elevated, mitochondrial membrane potential (MMP) and ATP were decreased in As-exposed MLE-12 cells. Mitoquinone mesylate (MitoQ), a novel mitochondrial-targeted antioxidant, alleviated As-induced excess mtROS, mitochondrial stress, MAMs dysfunction in pulmonary epithelial cells. Similarly, in vivo experiments indicated that MitoQ pretreatment countered As-induced pulmonary ferroptosis and ALI. These data indicated that mtROS-initiated MAMs dysfunction is, at least partially, implicated in As-evoked ferroptosis and ALI.
Insights
Arsenic exposure causes lung injury by triggering ferroptosis, a process linked to mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction. Targeting mitochondrial reactive oxygen species (mtROS) and MAMs dysfunction may protect against arsenic-induced lung damage.
Area of Science:
- Toxicology
- Cell Biology
- Pulmonary Medicine
Background:
- Arsenic (As) exposure is a significant environmental hazard linked to various health issues, including lung injury.
- Mitochondria-associated endoplasmic reticulum membranes (MAMs) play a crucial role in cellular homeostasis and their dysfunction is implicated in various pathologies.
- Ferroptosis, a regulated form of cell death driven by iron accumulation and lipid peroxidation, is increasingly recognized as a contributor to tissue injury.
Purpose of the Study:
- To investigate the role of mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction in arsenic-evoked pulmonary ferroptosis and acute lung injury (ALI).
- To elucidate the underlying molecular mechanisms connecting arsenic exposure, MAMs dysfunction, and ferroptosis in lung epithelial cells.
Main Methods:
- Mice and pulmonary epithelial cells (MLE-12) were exposed to arsenic (As).
- Ferroptosis inhibitor (Fer-1), PERK inhibitor, Mfn-2 overexpression, and mitochondrial-targeted antioxidant (MitoQ) were used to assess protective effects.
- Key markers of ferroptosis (e.g., ferritin, GPX4), iron deposition, mitochondrial function (mtROS, MMP, ATP), mitochondrial stress (CLPP, mtHSP70), and MAMs integrity were analyzed.
Main Results:
- Arsenic exposure induced ALI, characterized by alveolar damage, inflammation, and impaired lung function, alongside increased ferritin and decreased GPX4, indicating ferroptosis.
- Ferrostatin-1 (Fer-1) pretreatment alleviated As-induced ALI, iron deposition, mitochondrial damage, and ferroptosis.
- Arsenic exposure led to PERK phosphorylation, Mfn-2 reduction, impaired PERK-Mfn-2 interaction, and MAMs dysfunction, which were mitigated by PERK inhibition or Mfn-2 overexpression.
- Mitoquinone mesylate (MitoQ) effectively reduced As-induced mtROS, mitochondrial stress, and MAMs dysfunction, thereby protecting against pulmonary ferroptosis and ALI.
Conclusions:
- Mitochondria-associated endoplasmic reticulum membrane (MAMs) dysfunction, initiated by mitochondrial ROS (mtROS), plays a significant role in arsenic-evoked pulmonary ferroptosis and acute lung injury.
- Targeting mtROS and restoring MAMs integrity presents a potential therapeutic strategy for mitigating arsenic-induced lung damage.
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