Cellular ROS and Antioxidants: Physiological and Pathological Role.

Reactive oxygen species (ROS) are highly reactive oxygen derivatives that include free radicals such as superoxide anion radical (O2•-) and hydroxyl radical (HO•), as well as non-radical molecules hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hypochlorous acid (HOCl) [...].

Recent progresses in natural based therapeutic materials for Alzheimer's disease.

Alzheimer's disease is a neurological disorder that causes increased memory loss, mood swings, behavioral disorders, and disruptions in daily activities. Polymer scaffolds for the brain have been grown under laboratory, physiological, and pathological circumstances because of the limitations of conventional treatments for patients with central nervous system diseases. The blood-brain barrier prevents medications from entering the brain, challenging AD treatment. Numerous biomaterials such as biomolecules, polymers, inorganic metals, and metal oxide nanoparticles have been used to transport therapeutic medicines into the nervous system. Incorporating biocompatible materials that support neurogenesis through a combination of topographical, pharmacological, and mechanical stimuli has also shown promise for the transfer of cells to replenish dopaminergic neurons. Components made of naturally occurring biodegradable polymers are appropriate for the regeneration of nerve tissue. The ability of natural-based materials (biomaterials) has been shown to promote endogenous cell development after implantation. Also, strategic functionalization of polymeric nanocarriers could be employed for treating AD. In particular, nanoparticles could resolve Aß aggregation and thus help cure Alzheimer's disease. Drug moieties can be effectively directed to the brain by utilizing nano-based systems and diverse colloidal carriers, including hydrogels and biodegradable scaffolds. Notably, early investigations employing neural stem cells have yielded promising results, further emphasizing the potential advancements in this field. Few studies have fully leveraged the combination of cells with cutting-edge biomaterials. This study provides a comprehensive overview of prior research, highlighting the pivotal role of biomaterials as sophisticated drug carriers. It delves into various intelligent drug delivery systems, encompassing pH and thermo-triggered mechanisms, polymeric and lipid carriers, inorganic nanoparticles, and other vectors. The discussion synthesizes existing knowledge and underscores the transformative impact of these biomaterials in devising innovative strategies, augmenting current therapeutic methodologies, and shaping new paradigms in the realm of Alzheimer's disease treatment.

The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro.

Optic atrophy-1 (OPA1) plays a crucial role in the regulation of mitochondria fusion and participates in maintaining the structural integrity of mitochondrial cristae. Here we elucidate the role of OPA1 cleavage induced by calcium swelling in the presence of Myls22 (an OPA1 GTPase activity inhibitor) and TPEN (an OMA1 inhibitor). The rate of ADP-stimulated respiration was found diminished by both inhibitors, and they did not prevent Ca2+-induced mitochondrial respiratory dysfunction, membrane depolarization, or swelling. L-OPA1 cleavage was stimulated at state 3 respiration; therefore, our data suggest that L-OPA1 cleavage produces S-OPA1 to maintain mitochondrial bioenergetics in response to stress.

Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.

Mitochondrion, known as the "powerhouse" of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K+ and Ca2+, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes.

Amyloid ß induces cardiac dysfunction and neuro-signaling impairment in the heart of an Alzheimer's disease model.

Aims: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by cerebral amyloid ß (Aß) deposition and tau pathology. The AD-mediated degeneration of the brain neuro-signaling pathways, together with a potential peripheral amyloid accumulation, may also result in the derangement of the peripheral nervous system, culminating in detrimental effects on other organs, including the heart. However, whether and how AD pathology modulates cardiac function, neurotrophins, innervation, and amyloidosis is still unknown. Here, we report for the first time that cardiac remodeling, amyloid deposition, and neuro-signaling dysregulation occur in the heart of Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Methods ad Results: Echocardiographic analysis showed significant deterioration of left ventricle function, evidenced by a decline of both ejection fraction and fraction shortening percentage in 12-month-old Tg2576 mice compared to age-matched WT littermates. Tg2576 mice hearts exhibited an accumulation of amyloid aggregates, including Aß, an increase in interstitial fibrosis and severe cardiac nervous system dysfunction. The transgenic mice also showed a significant decrease in cardiac nerve fiber density, including both adrenergic and regenerating nerve endings. This myocardial denervation was accompanied by a robust reduction in NGF and BDNF protein expression as well as GAP-43 expression (regenerating fibers) in both the brain and heart of Tg2576 mice. Accordingly, cardiomyocytes and neuronal cells challenged with Aß oligomers showed significant downregulation of BDNF and GAP-43, indicating a causal effect of Aß on the loss of cardiac neurotrophic function. Conclusions: Overall, this study uncovers possible harmful effects of AD on the heart, revealing cardiac degeneration induced by Aß through fibrosis and neuro-signaling pathway deregulation for the first time in Tg2576 mice. Our data suggest that AD pathology can cause deleterious effects on the heart, and the peripheral neurotrophic pathway may represent a potential therapeutic target to limit these effects.

Unraveling the mechanisms of cardiolipin function: The role of oxidative polymerization of unsaturated acyl chains.

Cardiolipin is a unique phospholipid of the inner mitochondrial membrane (IMM) as well as in bacteria. It performs several vital functions such as resisting osmotic rupture and stabilizing the supramolecular structure of large membrane proteins, like ATP synthases and respirasomes. The process of cardiolipin biosynthesis results in the production of immature cardiolipin. A subsequent step is required for its maturation when its acyl groups are replaced with unsaturated acyl chains, primarily linoleic acid. Linoleic acid is the major fatty acid of cardiolipin across all organs and tissues, except for the brain. Linoleic acid is not synthesized by mammalian cells. It has the unique ability to undergo oxidative polymerization at a moderately accelerated rate compared to other unsaturated fatty acids. This property can enable cardiolipin to form covalently bonded net-like structures essential for maintaining the complex geometry of the IMM and gluing the quaternary structure of large IMM protein complexes. Unlike triglycerides, phospholipids possess only two covalently linked acyl chains, which constrain their capacity to develop robust and complicated structures through oxidative polymerization of unsaturated acyl chains. Cardiolipin, on the other hand, has four fatty acids at its disposal to form covalently bonded polymer structures. Despite its significance, the oxidative polymerization of cardiolipin has been overlooked due to the negative perception surrounding biological oxidation and methodological difficulties. Here, we discuss an intriguing hypothesis that oxidative polymerization of cardiolipin is essential for the structure and function of cardiolipin in the IMM in physiological conditions. In addition, we highlight current challenges associated with the identification and characterization of oxidative polymerization of cardiolipin in vivo. Altogether, the study provides a better understanding of the structural and functional role of cardiolipin in mitochondria.

The Effects of Amyloid-ß on Metabolomic Profiles of Cardiomyocytes and Coronary Endothelial Cells.

BACKGROUND: An increasing number of experimental and clinical studies show a link between Alzheimer's disease and heart diseases such as heart failure, ischemic heart disease, and atrial fibrillation. However, the mechanisms underlying the potential role of amyloid-ß (Aß) in the pathogenesis of cardiac dysfunction in Alzheimer's disease remain unknown. We have recently shown the effects of Aß1 - 40 and Aß1 - 42 on cell viability and mitochondrial function in cardiomyocytes and coronary artery endothelial cells. OBJECTIVE: In this study, we investigated the effects of Aß1 - 40 and Aß1 - 42 on the metabolism of cardiomyocytes and coronary artery endothelial cells. METHODS: Gas chromatography-mass spectrometry was used to analyze metabolomic profiles of cardiomyocytes and coronary artery endothelial cells treated with Aß1 - 40 and Aß1 - 42. In addition, we determined mitochondrial respiration and lipid peroxidation in these cells. RESULTS: We found that the metabolism of different amino acids was affected by Aß1 - 42 in each cell type, whereas the fatty acid metabolism is consistently disrupted in both types of cells. Lipid peroxidation was significantly increased, whereas mitochondrial respiration was reduced in both cell types in response to Aß1 - 42. CONCLUSION: This study revealed the disruptive effects of Aß on lipid metabolism and mitochondria function in cardiac cells.

Crosstalk between adenine nucleotide transporter and mitochondrial swelling: experimental and computational approaches.

Mitochondrial metabolism and function are modulated by changes in matrix Ca2+. Small increases in the matrix Ca2+ stimulate mitochondrial bioenergetics, whereas excessive Ca2+ leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca2+ overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FOF1-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANTM), cytosolic (ANTC), and pore (ANTP) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca2+ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca2+ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca2+ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca2+, enabled the model to simulate Ca2+ release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.

Mitochondria and ferroptosis.

Ferroptosis is a regulated iron-dependent cell death mechanism accompanied by the accumulation of peroxidized phospholipids, particularly phosphatidylethanolamine, in the cell. It occurs due to the disbalance between production and elimination of oxidized phospholipids in response to ferroptotic stimuli. A growing body of recent studies indicates that ferroptosis is involved in the pathogenesis of various human diseases leading to organ/tissue abnormalities. Due to their central role in ATP synthesis, ROS production, iron homeostasis, and redox status, mitochondria have been proposed to mediate ferroptotic signaling pathways. However, precise mechanisms underlying the potential role of mitochondria in ferroptosis remain unrevealed. This review summarizes and discusses previous studies on the contribution of mitochondria to ferroptotic cell death and highlights future directions elucidating the mitochondria as a promising target to prevent cell death through blocking ferroptosis.

Effects of Ferroptosis on the Metabolome in Cardiac Cells: The Role of Glutaminolysis.

Ferroptosis is a novel iron-dependent regulated cell death mechanism that affects cell metabolism; however, a detailed metabolomic analysis of ferroptotic cells is not yet available. Here, we elucidated the metabolome of H9c2 cardioblasts by gas chromatography-mass spectrometry during ferroptosis induced by RSL3, a GPX4 inhibitor, in the presence of ferrostatin-1 (a ferroptosis inhibitor), XJB-5-131 (a mitochondrial-targeted ROS scavenger), or TSM-1005-44 (a newly developed cellular ROS scavenger). Results demonstrated that RSL3 decreased the levels of amino acids involved in glutathione synthesis more than two-fold. In contrast, saturated fatty acids levels were markedly increased in RSL3-challenged cells, with no effects on unsaturated fatty acids. RSL3 significantly altered the levels of mitochondrial tricarboxylic acid cycle intermediates; isocitrate and 2-oxoglutarate were found to increase, whereas succinate was significantly decreased in RSL3-challenged cells. Ferrostatin-1, XJB-5-131, and TSM-1005-44 prevented RSL3-induced cell death and conserved the metabolomic profile of the cells. Since 2-oxoglutarate is involved in the regulation of ferroptosis, particularly through glutamine metabolism, we further assessed the role of glutaminolysis in ferroptosis in H9c2 cardioblasts. Genetic silencing of GLS1, which encodes the K-type mitochondrial glutaminase (glutaminase C), protected against ferroptosis in the early stage. In conclusion, our study demonstrates that RSL3-induced ferroptosis impairs the metabolome of H9c2 cardioblasts.

Analysis of Mitochondrial Function, Structure, and Intracellular Organization In Situ in Cardiomyocytes and Skeletal Muscles.

Analysis of the function, structure, and intracellular organization of mitochondria is important for elucidating energy metabolism and intracellular energy transfer. In addition, basic and clinically oriented studies that investigate organ/tissue/cell dysfunction in various human diseases, including myopathies, cardiac/brain ischemia-reperfusion injuries, neurodegenerative diseases, cancer, and aging, require precise estimation of mitochondrial function. It should be noted that the main metabolic and functional characteristics of mitochondria obtained in situ (in permeabilized cells and tissue samples) and in vitro (in isolated organelles) are quite different, thereby compromising interpretations of experimental and clinical data. These differences are explained by the existence of the mitochondrial network, which possesses multiple interactions between the cytoplasm and other subcellular organelles. Metabolic and functional crosstalk between mitochondria and extra-mitochondrial cellular environments plays a crucial role in the regulation of mitochondrial metabolism and physiology. Therefore, it is important to analyze mitochondria in vivo or in situ without their isolation from the natural cellular environment. This review summarizes previous studies and discusses existing approaches and methods for the analysis of mitochondrial function, structure, and intracellular organization in situ.

Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells.

Alzheimer's disease (AD) includes the formation of extracellular deposits comprising aggregated ß-amyloid (Aß) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aß in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aß1-40 and Aß1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aß1-40 and Aß1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aß1-42 had more adverse effects than Aß1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aß1-42. Mitochondrial dysfunction induced by Aß was associated with apoptosis of the cells. The effects of Aß1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aß1-40 and Aß1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aß on cell survival and mitochondria function in cardiac cells.

Analysis of Mitochondrial Calcium Retention Capacity in Cultured Cells: Permeabilized Cells Versus Isolated Mitochondria.

In response to various pathological stimuli, such as oxidative and energy stress accompanied by high Ca2+, mitochondria undergo permeability transition (PT) leading to the opening of the non-selective PT pores (PTP) in the inner mitochondrial membrane. Opening of the pores at high conductance allows the passage of ions and solutes <1.5 kD across the membrane, that increases colloid osmotic pressure in the matrix leading to excessive mitochondrial swelling. Calcium retention capacity (CRC) reflects maximum Ca2+ overload of mitochondria that occurs just before PTP opening. Quantification of CRC is important for elucidating the effects of different pathological stimuli and the efficacy of pharmacological agents on the mitochondria. Here, we performed a comparative analysis of CRC in mitochondria isolated from H9c2 cardioblasts, and in permeabilized H9c2 cells in situ to highlight the strengths and weaknesses of the CRC technique in isolated cell mitochondria vs. permeabilized cells. The cells were permeabilized by digitonin or saponin, and the Ca2+-sensitive fluorescence probe Calcium Green-5N was used in both preparations. Results demonstrated the interference of dye-associated fluorescence signals with saponin and the adverse effects of digitonin on mitochondria at high concentrations. Analysis of the CRC in permeabilized cells revealed a higher CRC in the saponin-permeabilized cells in comparison with the digitonin-permeabilized cells. In addition, the mitochondrial CRC in saponin-permeabilized cells was higher than in isolated mitochondria. Altogether, these data demonstrate that the quantification of the mitochondrial CRC in cultured cells permeabilized by saponin has more advantages compared to the isolated mitochondria.

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid ß (Aß) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aß also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood-brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aß-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes.

Ferroptosis is a programmed iron-dependent cell death associated with peroxidation of lipids particularly, phospholipids. Several studies suggested a possible contribution of mitochondria to ferroptosis although the mechanisms underlying mitochondria-mediated ferroptotic pathways remain elusive. Reduced glutathione (GSH) is a central player in ferroptosis that is required for glutathione peroxidase 4 to eliminate oxidized phospholipids. Mitochondria do not produce GSH, and although the transport of GSH to mitochondria is not fully understood, two carrier proteins, the dicarboxylate carrier (DIC, SLC25A10) and the oxoglutarate carrier (OGC, SLC25A11) have been suggested to participate in GSH transport. Here, we elucidated the role of DIC and OGC as well as mitochondrial bioenergetics in ferroptosis in H9c2 cardioblasts. Results showed that mitochondria are highly sensitive to ferroptotic stimuli displaying fragmentation, and lipid peroxidation shortly after the onset of ferroptotic stimulus. Inhibition of electron transport chain complexes and oxidative phosphorylation worsened RSL3-induced ferroptosis. LC-MS/MS analysis revealed a dramatic increase in the levels of pro-ferroptotic oxygenated phosphatidylethanolamine species in mitochondria in response to RSL3 (ferroptosis inducer) and cardiac ischemia-reperfusion. Inhibition of DIC and OGC aggravated ferroptosis and increased mitochondrial ROS, membrane depolarization, and GSH depletion. Dihydrolipoic acid, an essential cofactor for several mitochondrial multienzyme complexes, attenuated ferroptosis and induced direct reduction of pro-ferroptotic peroxidized phospholipids to hydroxy-phospholipids in vitro. In conclusion, we suggest that ferroptotic stimuli diminishes mitochondrial bioenergetics and stimulates GSH depletion and glutathione peroxidase 4 inactivation leading to ferroptosis.

Direct Mapping of Phospholipid Ferroptotic Death Signals in Cells and Tissues by Gas Cluster Ion Beam Secondary Ion Mass Spectrometry (GCIB-SIMS).

Peroxidized phosphatidylethanolamine (PEox) species have been identified by liquid chromatography mass spectrometry (LC-MS) as predictive biomarkers of ferroptosis, a new program of regulated cell death. However, the presence and subcellular distribution of PEox in specific cell types and tissues have not been directly detected by imaging protocols. By applying gas cluster ion beam secondary ion mass spectrometry (GCIB-SIMS) imaging with a 70 keV (H2 O)n+ (n>28 000) cluster ion beam, we were able to map PEox with 1.2 µm spatial resolution at the single cell/subcellular level in ferroptotic H9c2 cardiomyocytes and cortical/hippocampal neurons after traumatic brain injury. Application of this protocol affords visualization of physiologically relevant levels of very low abundance (20 pmol µmol-1 lipid) peroxidized lipids in subcellular compartments and their accumulation in disease conditions.

Structural and functional remodeling of mitochondria as an adaptive response to energy deprivation.

Cancer cells bioenergetics is more dependent on glycolysis than mitochondrial oxidative phosphorylation, a phenomenon known as the Warburg Effect. It has been proposed that inhibition of glycolysis may selectively affect cancer cells. However, the effects of glycolysis inhibition on mitochondrial function and structure in cancer cells are not completely understood. Here, we investigated the comparative effects of 2-deoxy-d-glucose (2-DG, a glucose analogue, which suppresses cellular glycolysis) on cellular bioenergetics in human colon cancer DLD-1 cells, smooth muscle cells, human umbilical vein endothelial cells and HL-1 cardiomyocytes. In all cells, 2-DG treatment resulted in significant ATP depletion, however, the cell viability remained unchanged. Also, we did not observe the synergistic effects of 2-DG with anticancer drugs doxorubicin and 5-fluorouracil. Instead, after 2-DG treatment and ATP depletion, mitochondrial respiration and membrane potential were significantly enhanced and mitochondrial morphology changed in the direction of more network organization. Analysis of protein expression demonstrated that 2-DG treatment induced an activation of AMPK (elevated pAMPK/AMPK ratio), increased mitochondrial fusion (mitofusins 1 and 2) and decreased fission (Drp1) proteins. In conclusion, this study suggests a strong link between respiratory function and structural organization of mitochondria in the cell. We propose that the functionality of the mitochondrial network is enhanced compared to disconnected mitochondria.

Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role.

Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.

Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats.

BACKGROUND/AIMS: Structural and functional alterations in mitochondria, particularly, the inner mitochondrial membrane (IMM) plays a critical role in mitochondria-mediated cell death in response to cardiac ischemia-reperfusion (IR) injury. The integrity of IMM can be affected by two potential intra-mitochondrial factors: i) mitochondrial matrix swelling, and ii) proteolytic cleavage of the long optic atrophy type 1 (L-OPA1), an IMM-localized dynamin-like GTPase engaged in the regulation of structural organization and integrity of the mitochondrial cristae. However, the relationship between these two factors in response to oxidative stress remains unclear. Here, we elucidated the effects of cardiac IR injury on L-OPA1 cleavage and OMA1 activity. METHODS: Langendorff-mode perfused isolated rat hearts were subjected to 25-min of global ischemia followed by 90-min reperfusion in the presence or absence of XJB-5-131 (XJB, a mitochondria-targeting ROS scavenger) and sanglifehrin A (SfA, a permeability transition pore inhibitor). RESULTS: XJB in combination with SfA increased post-ischemic recovery of cardiac function and reduced mitochondrial ROS production at 30- and 60-min reperfusion and affected mitochondrial swelling. L-OPA1 levels were reduced in IR hearts; however, neither XJB, SfA, and their combination prevented IR-induced reduction of L-OPA1 cleavage. Likewise, IR increased the OMA1 enzymatic activity, which remained unchanged in the presence of XJB and/or SfA. CONCLUSION: IR-induced cardiac and mitochondrial dysfunctions are associated with OMA1 activation and L-OPA1 cleavage. However, XJB, SfA, and their combination do not prevent these changes despite improved heart and mitochondria function, thus, suggesting that different mechanisms can be implicated in L-OPA1 processing in response to cardiac IR injury.

Mitochondria in Health and Diseases.

Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play a pivotal role in cell life and cell death. Mitochondria are engaged in the pathogenesis of human diseases and aging directly or indirectly through a broad range of signaling pathways. However, despite an increased interest in mitochondria over the past decades, the mechanisms of mitochondria-mediated cell/organ dysfunction in response to pathological stimuli remain unknown. The Special Issue, "Mitochondria in Health and Diseases," organized by Cells includes 24 review and original articles that highlight the latest achievements in elucidating the role of mitochondria under physiological (healthy) conditions and, in various cell/animal models of human diseases and, in patients. Altogether, the Special Issue summarizes and discusses different aspects of mitochondrial metabolism and function that open new avenues in understanding mitochondrial biology.