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Short-term impairment of energy production in isolated rat liver mitochondria by hypoxia/reoxygenation: involvement of oxidative protein modification.

ABSTRACT: The aim of the present study was to elucidate the role of mitochondria in liver impairment after ischaemia/reperfusion. It is commonly assumed that mitochondria are in part responsible for tissue damage by impaired oxidative phosphorylation as a consequence of the attack of radicals generated within the mitochondria. The principal support for this hypothesis was found by exposing isolated mitochondria to temporary hypoxia in combination with alterations of substrate supply. Rat liver mitochondria treated in this way responded with impaired ADP-stimulated respiration after reoxygenation, which decreased with time of hypoxia and reoxygenation. The decline of the activity of the NADH-cytochrome c-oxidoreductase complex found under these conditions is likely to cause the drop in active respiration. No changes in the content of respiratory chain complexes, determined by Blue Native PAGE, could be demonstrated. However, oxidative modifications of mitochondrial proteins, indicated by carbonyl formation, were found. Likewise, products of lipid peroxidation, such as lipid peroxides and malondialdehyde, were formed. Mitochondria were still able to build up a transmembrane potential and did not show drastic changes in membrane conductivity after hypoxia/reoxygenation stress. The presence of water-soluble antioxidants exhibited a beneficial effect, diminishing the decline of active respiration after 5 min of hypoxia and 10 min of reoxygenation. These observations strongly suggest that mitochondria play a pathogenic role in ischaemia/reperfusion injury, which is at least in part mediated by an oxygen-derived free-radical-linked mechanism.

SUBMITTER: Schild L

PROVIDER: S-EPMC1218907 | biostudies-other | 1997 Nov

REPOSITORIES: biostudies-other

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Adenosine signaling mediates SUMO-1 modification of IkappaBalpha during hypoxia and reoxygenation.

Project description:Small ubiquitin-like modifier 1 (SUMO-1) modification of IkappaBalpha has been described to actively participate in NFkappaB regulation. Following proteosomal degradation of IkappaBalpha, an auto-regulatory loop consisting of transcriptional activation of IkappaBalpha gene and SUMO-1 modification of newly synthesized IkappaBalpha proceeds. The SUMOylated IkappaBalpha form is resistant to signal-induced degradation, consequently halting NFkappaB activation. We describe a mechanistic model by which adenosine (Ado) signaling results in significant accumulation of SUMO-1 modified IkappaBalpha with subsequent attenuation of NFkappaB activation. Using models of hypoxia followed by reoxygenation (H/R), we have documented an H/R cycle-dependent increase in extracellular Ado correlating with increases in the cytoplasmic pool of IkappaBalpha/SUMO-1. We demonstrate a dose-dependent increase in IkappaBalpha/SUMO in cells treated with the general Ado receptor agonist NECA and abolished by Ado receptor antagonists. Experiments in cells exposed to cycles of H/R followed by hypoxia demonstrated differential patterns of SUMOylation and phosphorylation of IkappaBalpha, greatly impacting its proteosomal degradation by the 26 S proteasome. Assays targeting knockdown and overexpression of SUMO-1 demonstrated significant regulation of NFkappaB activation and NFkappaB-mediated gene transcription (interleukin-6). These results were confirmed in vivo using wild type and cd73 null mouse lung tissue. In summary, we present an endogenous mechanism by which cells and tissues acquire anti-inflammatory properties by recruiting a nondegradable form of IkappaBalpha, a major control point for NFkappaB activation via Ado signaling.

| S-EPMC2679470 | biostudies-literature

Liquiritin from <i>Radix Glycyrrhizae</i> Protects Cardiac Mitochondria from Hypoxia/Reoxygenation Damage.

Project description:AimsThe purpose of this study was to evaluate the protective effect of liquiritin (LIQ) from Radix Glycyrrhizae on cardiac mitochondria against hypoxia/reoxygenation (HR) injury.MethodsH9C2 cells were subject to the HR model. LIQ purified from Radix Glycyrrhizae (purity > 95%) was administrated to reoxygenation period. Cell viability, mitochondrial mass, mitochondrial membrane potential, reactive oxygen species, and mitochondrial Ca2⁺ level were then assessed by using Cell Counting kit-8 and suitable fluorescence probe kits.ResultsLIQ administration remarkably reduced the rate of HR damage via increasing H9C2 cell viability level and preserving mitochondria after HR. Particularly, 60 μM of LIQ posthypoxic treatment markedly reduced cell death in HR-subjected H9C2 cell groups (p < 0.05). Interestingly, posthypoxic treatment of LIQ significantly prevented the loss of mitochondrial membrane potential, the decrease in mitochondrial mass, the increase in reactive oxygen species production, and the elevation of mitochondrial Ca2⁺ level in HR-treated H9C2 cells.ConclusionThe present study provides for the first time the cardioprotective of LIQ posthypoxic treatment via reducing H9C2 cell death and protecting cardiac mitochondria against HR damage.

| S-EPMC8369190 | biostudies-literature

Altered fusion dynamics underlie unique morphological changes in mitochondria during hypoxia-reoxygenation stress.

Project description:Functional states of mitochondria are often reflected in characteristic mitochondrial morphology. One of the most fundamental stress conditions, hypoxia-reoxygenation has been known to cause impaired mitochondrial function accompanied by structural abnormalities, but the underlying mechanisms need further investigation. Here, we monitored bioenergetics and mitochondrial fusion-fission in real time to determine how changes in mitochondrial dynamics contribute to structural abnormalities during hypoxia-reoxygenation. Hypoxia-reoxygenation resulted in the appearance of shorter mitochondria and a decrease in fusion activity. This fusion inhibition was a result of impaired ATP synthesis rather than Opa1 cleavage. A striking feature that appeared during hypoxia in glucose-free and during reoxygenation in glucose-containing medium was the formation of donut-shaped (toroidal) mitochondria. Donut formation was triggered by opening of the permeability transition pore or K(+) channels, which in turn caused mitochondrial swelling and partial detachment from the cytoskeleton. This then favored anomalous fusion events (autofusion and fusion at several sites among 2-3 mitochondria) to produce the characteristic donuts. Donuts effectively tolerate matrix volume increases and give rise to offspring that can regain ΔΨ(m). Thus, the metabolic stress during hypoxia-reoxygenation alters mitochondrial morphology by inducing distinct patterns of mitochondrial dynamics, which includes processes that could aid mitochondrial adaptation and functional recovery.

| S-EPMC3172112 | biostudies-literature

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90.

Project description:Modulation of oxidative stress is therapeutically effective in ischemia/reperfusion (I/R) injury. Myricitrin, a naturally occurring phenolic compound, is a potent antioxidant. However, little is known about its effect on I/R injury to cardiac myocytes. The present study was performed to investigate the potential protective effect of myricitrin against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. Myricitrin pretreatment improved cardiomyocyte viability, inhibited ROS generation, maintained the mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased the caspase-3 activity, upregulated antiapoptotic proteins and downregulated proapoptotic proteins during H/R injury. Moreover, the potential targets of myricitrin was predicted using Discovery Studio software, and heat shock protein 90 (Hsp90) was identified as the main disease-related target. Further mechanistic investigation revealed that 17-AAG, a pharmacologic inhibitor of Hsp90, significantly blocked the myricitrin-induced cardioprotective effect demonstrated by increased apoptosis and ROS generation. These results suggested that myricitrin provides protection to H9c2 cardiomyocytes against H/R-induced oxidative stress and apoptosis, most likely via increased expression of Hsp90.

| S-EPMC5462924 | biostudies-literature

Clematichinenoside (AR) Attenuates Hypoxia/Reoxygenation-Induced H9c2 Cardiomyocyte Apoptosis via a Mitochondria-Mediated Signaling Pathway.

Project description:Mitochondria-mediated cardiomyocyte apoptosis is involved in myocardial ischemia/reperfusion (MI/R) injury. Clematichinenoside (AR) is a triterpenoid saponin isolated from the roots of Clematis chinensis with antioxidant and anti-inflammatory cardioprotection effects against MI/R injury, yet the anti-apoptotic effect and underlying mechanisms of AR in MI/R injury remain unclear. We hypothesize that AR may improve mitochondrial function to inhibit MI/R-induced cardiomyocyte apoptosis. In this study, we replicated an in vitro H9c2 cardiomyocyte MI/R model by hypoxia/reoxygenation (H/R) treatment. The viability of H9c2 cardiomyocytes was determined by MTT assay; apoptosis was evaluated by flow cytometry and TUNEL experiments; mitochondrial permeability transition pore (mPTP) opening was analyzed by a calcein-cobalt quenching method; and mitochondrial membrane potential (??m) was detected by JC-1. Moreover, we used western blots to determine the mitochondrial cytochrome c translocation to cytosolic and the expression of caspase-3, Bcl-2, and Bax proteins. These results showed that the application of AR decreased the ratio of apoptosis and the extent of mPTP opening, but increased ??m. AR also inhibited H/R-induced release of mitochondrial cytochrome c and decreased the expression of the caspase-3, Bax proteins. Conversely, it remarkably increased the expression of Bcl-2 protein. Taken together, these results revealed that AR protects H9c2 cardiomyocytes against H/R-induced apoptosis through mitochondrial-mediated apoptotic signaling pathway.

| S-EPMC6273438 | biostudies-literature

Reactive oxygen species production in energized cardiac mitochondria during hypoxia/reoxygenation: modulation by nitric oxide.

Project description:Mitochondria are an important source of reactive oxygen species (ROS), implicated in ischemia/reperfusion injury. When isolated from ischemic myocardium, mitochondria demonstrate increased ROS production as a result of damage to electron transport complexes. To investigate the mechanisms, we studied effects of hypoxia/reoxygenation on ROS production by isolated energized heart mitochondria. ROS production, tracked using Fe(2+)-catalyzed, H(2)O(2)-dependent H(2)DCF oxidation or Amplex Red, was similar during normoxia and hypoxia but markedly increased during reoxygenation, in proportion to the duration of hypoxia. In contrast, if mitochondria were rapidly converted from normoxia to near-anoxia ([O(2)], <1 micromol/L), the increase in H(2)DCF oxidation rate during reoxygenation was markedly blunted. To elicit the robust increase in H(2)DCF oxidation rate during reoxygenation, hypoxia had to be severe enough to cause partial, but not complete, respiratory chain inhibition (as shown by partial dissipation of membrane potential and increased NADH autofluorescence). Consistent with its cardioprotective actions, nitric oxide ( O) abrogated increased H(2)DCF oxidation under these conditions, as well as attenuating ROS-induced increases in matrix [Fe(2+)] and aconitase inhibition caused by antimycin. Collectively, these results suggest that (1) hypoxia that is sufficient to cause partial respiratory inhibition is more damaging to mitochondria than near-anoxia; and (2) O suppresses ROS-induced damage to electron transport complexes, probably by forming O-Fe(2+) complexes in the presence of glutathione, which inhibit hydroxyl radical formation.

| S-EPMC2755534 | biostudies-literature

Transcription profiling of Arabidopsis after short and prolonged hypoxia and reoxygenation

Project description:Gene expression analysis of 7d-old Arabidopsis seedlings exposed to short term (2 h) hypoxia, long term (9 h) hypoxia, and 1 h reoxygenation after long term (9 h) hypoxia to evaluate the regulation of gene expression at the level of translation. Experiment Overall Design: 30 samples, 5 conditions (2 hr hypoxia stress, 2hr non-stress, 9 hr hypoxia stress , 9 hr non-stress, 9 hr hypoxia with 1 hr recovery), 2 RNA pools (Total mRNA and polysomal mRNA), 3 replicates

2008-10-20 | E-GEOD-9719 | biostudies-arrayexpress

[The Effect of Short-Term Intermittent Hypoxia Exposure on Mouse Myocardial Oxidative Stress and Cardiac Function].

Project description:ObjectiveTo investigate the effect of short-term intermittent hypoxia (IH) on the structure and function of mouse myocardium.MethodsThirty male C57BL6/J mice were randomly assigned to two groups, a control (Con) group and an IH group exposed to hypoxic treatment at atmospheric pressure. The IH group received 10% oxygen pretreatment for 8 hours per day on 14 consecutive days, while the Con group was exposed to normoxia environment and all the other treatment the group received were identical to those given to the IH group, The body mass of the mice was monitored daily during the treatment. The exercise tolerance and the cardiac function of isolated heart were assessed at the end of IH exposure. Additionally, analysis was conducted regarding myocardial enzymology, histology, and other indicators relevant to oxidative stress, including protein carbonylation and lipid peroxidation.ResultsThere was no significant difference in the exercise tolerance between the two groups. Nevertheless, IH mice showed enhanced cardiac function during isolated heart perfusion ( P<0.05). As compared to the control group, prominent alterations of myocardial structure were detected by transmission electron microscopy of the IH heart, accompanied by elevated creatine kinase-MB levels ( P<0.05). The levels of myocardial reactive oxygen species, protein carbonylation and lipid peroxidation were all significantly upregulated in the IH group as compared to the control group ( P<0.05).ConclusionIH exposure induced myocardial oxidative stress damage and myofibrillar structural alteration in mice, but did not impair the exercise tolerance of the mice or the contractile function of the isolated heart.

| S-EPMC10408848 | biostudies-literature

Quantum Sensing of Free Radical Generation in Mitochondria of Single Heart Muscle Cells during Hypoxia and Reoxygenation.

Project description:Cells are damaged during hypoxia (blood supply deprivation) and reoxygenation (oxygen return). This damage occurs in conditions such as cardiovascular diseases, cancer, and organ transplantation, potentially harming the tissue and organs. The role of free radicals in cellular metabolic reprogramming under hypoxia is under debate, but their measurement is challenging due to their short lifespan and limited diffusion range. In this study, we employed a quantum sensing technique to measure the real-time production of free radicals at the subcellular level. We utilize fluorescent nanodiamonds (FNDs) that exhibit changes in their optical properties based on the surrounding magnetic noise. This way, we were able to detect the presence of free radicals. To specifically monitor radical generation near mitochondria, we coated the FNDs with an antibody targeting voltage-dependent anion channel 2 (anti-VDAC2), which is located in the outer membrane of mitochondria. We observed a significant increase in the radical load on the mitochondrial membrane when cells were exposed to hypoxia. Subsequently, during reoxygenation, the levels of radicals gradually decreased back to the normoxia state. Overall, by applying a quantum sensing technique, the connections among hypoxia, free radicals, and the cellular redox status has been revealed.

| S-EPMC10832053 | biostudies-literature

Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis.

Project description:Exogenous ubiquitin (UB) plays a protective role in β-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3β was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.

| S-EPMC7416794 | biostudies-literature

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