Pathophysiological implications of mitochondrial oxidative stress mediated by mitochondriotropic agents and polyamines: the role of tyrosine phosphorylation

Abstract

Mitochondria, once merely considered as the "powerhouse" of cells, as they generate more than 90 % of cellular ATP, are now known to play a central role in many metabolic processes, including oxidative stress and apoptosis. More than 40 known human diseases are the result of excessive production of reactive oxygen species (ROS), bioenergetic collapse and dysregulated apoptosis. Mitochondria are the main source of ROS in cells, due to the activity of the respiratory chain. In normal physiological conditions, ROS generation is limited by the anti-oxidant enzymatic systems in mitochondria. However, disregulation of the activity of these enzymes or interaction of respiratory complexes with mitochondriotropic agents may lead to a rise in ROS concentrations, resulting in oxidative stress, mitochondrial permeability transition (MPT) induction and triggering of the apoptotic pathway. ROS concentration is also increased by the activity of amine oxidases located inside and outside mitochondria, with oxidation of biogenic amines and polyamines. However, it should also be recalled that, depending on its concentration, the polyamine spermine can also protect against stress caused by ROS scavenging. In higher organisms, cell signaling pathways are the main regulators in energy production, since they act at the level of mitochondrial oxidative phosphorylation and participate in the induction of the MPT. Thus, respiratory complexes, ATP synthase and transition pore components are the targets of tyrosine kinases and phosphatases. Increased ROS may also regulate the tyrosine phosphorylation of target proteins by activating Src kinases or phosphatases, preventing or inducing a number of pathological states.

Exogenous spermine preserves mitochondrial bioenergetics via regulating Src kinase signaling in the spinal cord

“…Considering that oxidative phosphorylation is the central target of SFKs (33), our first hypothesis deals with the possible effect of spermine in altering mitochondrial respiration, and the results appear to confirm this effect. In the measurement of respiration, state III reflects the maximum Figure 6.…”

Maize polyamine oxidase in the presence of spermine/spermidine induces the apoptosis of LoVo human colon adenocarcinoma cells

“…It is known that the mitochondria play a pivotal role in the intrinsic apoptotic pathway and a reduction in Δψ m is an early irreversible step (65). The observations reported in this study indicated that spermine metabolite-induced apoptosis was preceded by the Δψ m collapse in the LoVo cells (Fig.…”

“…However, although polyamine concentrations are upregulated in tumors, free polyamines which can be oxidized by ZmPAO are present only in small amounts as polyamines preferentially bind to macromolecules, such as DNA, RNA, and proteins (12). Moreover, slow and low ROS production may be completely removed by enzymes of the antioxidant system, such as catalase, glutathione peroxidase, and superoxide dismutase (65). A recent study demonstrated that recombinant ZmPAO overexpression in human breast cancer cells did not inhibit cell growth under normal growth conditions (64).…”

Aged garlic extract and its constituent, S‑allyl‑L‑cysteine, induce the apoptosis of neuroblastoma cancer cells due to mitochondrial membrane depolarization

“…8). It is known that the mitochondria play a pivotal role in the intrinsic apoptotic pathway and a reduction in Δψm is an early irreversible step (54). By labeling the NB cells with the probe JC-1 dye, cytofluorimetric analysis revealed that the target of SAC was the mitochondria.…”