4-Hydroxynonenal regulates mitochondrial function in human small airway epithelial cells

Abstract

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response.

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

“…According to our study, these lipid peroxidation by-products were significantly decreased in the hyperoxic P2X7 KO mice, indicating the protective effect of P2X7 deletion during hyperoxia-induced oxidative stress. 4-HNE and MDA are known to be additional markers of oxidative stress and are produced in response to increased levels of ROS (16). On the basis of our results, knockdown of P2X7 significantly reduced the production of these peroxidized lipid by-products, further signifying the importance of P2X7 deletion-mediated protection in HALI.…”

“…Indicators of oxidative stress like F2-isoprostanes and isofurans were estimated using Cayman 8-isoprostane ELISA kit (Ann Arbor, MI) using lung homogenates as per the manufacturer's instructions. Other protein adducts, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were analyzed by ELISA in lung tissue homogenates, as previously described (16).…”

The Protective Roles of ROS-Mediated Mitophagy on125I Seeds Radiation Induced Cell Death in HCT116 Cells

“…In addition to being the power center of the cell, mitochondria also generates reactive oxygen species (ROS), which originate from the electron leak from ETC. It has been well known that damage of mitochondria presented typical alterations in mitochondrial morphology accompanied by biochemical changes, such as decreased ATP, decreased mitochondrial membrane potential, and increased mitochondrial ROS [51]. We therefore measured mitochondrial parameters after exposure to 2 Gy of 125 I seeds radiation.…”

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

“…Oxygen radicals and products of lipid peroxidation can directly deteriorate mitochondrial function by inhibiting oxidative phosphorylation, by reducing membrane potential and aconitase activity in pulmonary epithelial cells (37). Mitochondria-targeted antioxidant, mitoTEMPO, attenuated the extent of hyperoxia-induced lung injury and right ventricular hypertrophy in neonatal mice (38).…”