Induction of the permeability transition and cytochrome c release by 15-deoxy-Δ12,14-prostaglandin J2 in mitochondria

Abstract

The electrophilic lipid 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) is known to allow adaptation to oxidative stress in cells at low concentrations and apoptosis at high levels. The mechanisms leading to adaptation involve the covalent modification of regulatory proteins, such as Keap1, and augmentation of antioxidant defences in the cell. The targets leading to apoptosis are less well defined, but mitochondria have been indirectly implicated in the mechanisms of cell death mediated by electrophilic lipids. To determine the potential of electrophilic cyclopentenones to induce pro-apoptotic effects in the mitochondrion, we used isolated liver mitochondria and demonstrated that 15d-PGJ2 promotes Ca2+-induced mitochondrial swelling and cytochrome c release. The mechanisms involved are consistent with direct modification of protein thiols in the mitochondrion, rather than secondary formation of reactive oxygen species or lipid peroxidation. Using proteomic analysis in combination with biotinylated 15d-PGJ2, we were able to identify 17 potential targets of the electrophile-responsive proteome in isolated liver mitochondria. Taken together, these results suggest that electrophilic lipid oxidation products can target a sub-proteome in mitochondria, and this in turn results in the transduction of the electrophilic stimulus to the cell through cytochrome c release.

Interaction of peroxidized cardiolipin with rat‐heart mitochondrial membranes: Induction of permeability transition and cytochrome c release

“…Thus, it is conceivable that peroxidized cardiolipin lowers the threshold of Ca 2+ for inducing MPT and/or potentiates the effect of this cation in MPT opening. Interestingly, the induction of pore opening in a similar manner, has also been reported for other reactive lipid peroxidation products, including 4-hydroxynonenal [29] and 15-deoxy-D 12-14 -prostaglandin J 2 [30] and is another example of the ''two hit'' hypothesis leading to pore opening [31]. The synergistic effect of Ca 2+ and peroxidized cardiolipin on the MPT induction, suggests that both these compounds play a coordinated role in this process, by interacting with components of MPT.…”

Decreased Bioenergetic Health Index in monocytes isolated from the pericardial fluid and blood of post-operative cardiac surgery patients

“…Both oxidized lipids and hydrogen peroxide are known to damage mitochondria [14,22]. For example, mitochondrial dysfunction is a major consequence of lipid peroxidation, promoted by haeme and haeme proteins and is characterized by irreversible permeabilization of the mitochondrial membrane, a decrease in membrane potential, loss of cellular bioenergetics and mitochondrial swelling [24][25][26][27][28]. These findings suggest that the severity of any mitochondrial defects correspond to the greatest exposure to oxidative stress, which in this case would be in the PO-PCF.…”

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Studies conducted by Darley-Usmar and colleagues [136] have demonstrated that the electrophilic lipid peroxidation product, 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), is capable of inducing apoptosis in liver mitochondria. According to the ,two hit' mechanism proposed by Brookes et al [132], electrophile stress potentiates opening of the PTP under conditions of elevated Ca 2+ levels in the mitochondrial matrix.…”