Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.     

Enhanced Expression of TRAP1 Protects Mitochondrial Function in Motor Neurons under Conditions of Oxidative Stress

TNF-receptor associated protein (TRAP1) is a cytoprotective mitochondrial-specific member of the Hsp90 heat shock protein family of protein chaperones that has been shown to antagonise mitochondrial apoptosis and oxidative stress, regulate the mitochondrial permeability transition pore and control protein folding in mitochondria. Here we show that overexpression of TRAP1 protects motor neurons from mitochondrial dysfunction and death induced by exposure to oxidative stress conditions modelling amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease in which motor neurons degenerate, leading to muscle weakness and atrophy and death, typically within 3 years of diagnosis. In primary murine motor neurons, shRNA-mediated knockdown of TRAP1 expression results in mitochondrial dysfunction but does not further exacerbate damage induced by oxidative stress alone. Together, these results show that TRAP1 may be a potential therapeutic target for neurodegenerative diseases such as ALS, where mitochondrial dysfunction has been shown to be an early marker of pathogenesis.     

Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration

Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD), a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA) damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA) may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age) when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis.     

Pathogenesis of Target Organ Damage in Hypertension: Role of Mitochondrial Oxidative Stress

Hypertension causes target organ damage (TOD) that involves vasculature, heart, brain and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS). Both in vitro and in vivo studies explored the role of mitochondrial oxidative stress as a mechanism involved in the pathogenesis of TOD in hypertension, especially focusing on atherosclerosis, heart disease, renal failure, cerebrovascular disease. Both dysfunction of mitochondrial proteins, such as uncoupling protein-2 (UCP2), superoxide dismutase (SOD) 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), calcium channels, and the interaction between mitochondria and other sources of ROS, such as NADPH oxidase, play an important role in the development of endothelial dysfunction, cardiac hypertrophy, renal and cerebral damage in hypertension. Commonly used anti-hypertensive drugs have shown protective effects against mitochondrial-dependent oxidative stress. Notably, few mitochondrial proteins can be considered therapeutic targets on their own. In fact, antioxidant therapies specifically targeted at mitochondria represent promising strategies to reduce mitochondrial dysfunction and related hypertensive TOD. In the present article, we discuss the role of mitochondrial oxidative stress as a contributing factor to hypertensive TOD development. We also provide an overview of mitochondria-based treatment strategies that may reveal useful to prevent TOD and reduce its progression.     

Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders

Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders.     

Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation

Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.     

Mitochondrion as a Target of Astaxanthin Therapy in Heart Failure

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.     

C60 Fullerene Reduces 3-Nitropropionic Acid-Induced Oxidative Stress Disorders and Mitochondrial Dysfunction in Rats by Modulation of p53, Bcl-2 and Nrf2 Targeted Proteins

C₆₀ fullerene as a potent free radical scavenger and antioxidant could be a beneficial means for neurodegenerative disease prevention or cure. The aim of the study was to define the effects of C₆₀ administration on mitochondrial dysfunction and oxidative stress disorders in a 3-nitropropionic acid (3-NPA)-induced rat model of Huntington’s disease. Animals received 3-NPA (30 mg/kg i.p.) once a day for 3 consecutive days. C₆₀ was applied at a dose of 0.5 mg/kg of body weight, i.p. daily over 5 days before (C₆₀ pre-treatment) and after 3-NPA exposure (C₆₀ post-treatment). Oxidative stress biomarkers, the activity of respiratory chain enzymes, the level of antioxidant defense, and pro- and antiapoptotic markers were analyzed in the brain and skeletal muscle mitochondria. The nuclear and cytosol Nrf2 protein expression, protein level of MnSOD, γ-glutamate-cysteine ligase (γ-GCLC), and glutathione-S-transferase (GSTP) as Nrf2 targets were evaluated. Our results indicated that C₆₀ can prevent 3-NPA-induced mitochondrial dysfunction through the restoring of mitochondrial complexes’ enzyme activity, ROS scavenging, modulating of pro/antioxidant balance and GSH/GSSG ratio, as well as inhibition of mitochondria-dependent apoptosis through the limitation of p53 mitochondrial translocation and increase in Bcl-2 protein expression. C₆₀ improved mitochondrial protection by strengthening the endogenous glutathione system via glutathione biosynthesis by up-regulating Nrf2 nuclear accumulation as well as GCLC and GSTP protein level.     

Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione–electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.     

Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases

Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders.     

Oxidative Stress and Its Significant Roles in Neurodegenerative Diseases and Cancer

Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizing carbonylated proteins reveal oxidative damage to heat shock proteins in neurodegenerative disease models and inflammation-related cancer, suggesting dysfunction in their antioxidative properties. In neurodegenerative diseases, DNA damage may not only play a role in the induction of apoptosis, but also may inhibit cellular division via telomere shortening. Immunohistochemical analyses showed co-localization of oxidative/nitrative DNA lesions and stemness markers in the cells of inflammation-related cancers. Here, we review oxidative stress and its significant roles in neurodegenerative diseases and cancer.     

Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression

While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H₂), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H₂ has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H₂ against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H₂ as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.     

Parkinson’s Disease: A Complex Interplay of Mitochondrial DNA Alterations and Oxidative Stress

Parkinson’s disease (PD) is one of the most common age-related neurodegenerative diseases. This pathology causes a significant loss of dopaminergic neurons in the Substantia Nigra. Several reports have claimed a role of defective nuclear and mitochondrial DNA repair pathways in PD etiology, in particular, of the Base Excision Repair (BER) system. In addition, recent findings, related to PD progression, indicate that oxidative stress pathways involving c-Abl and GST could also be implicated in this pathology. This review focuses on recently described networks most likely involved in an integrated manner in the course of PD.     

Oxidative Stress in Diabetes: Implications for Vascular and Other Complications

In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the “final common pathway” through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell–cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients.     

Mitochondrial Oxidative Stress—A Causative Factor and Therapeutic Target in Many Diseases

The excessive formation of reactive oxygen species (ROS) and impairment of defensive antioxidant systems leads to a condition known as oxidative stress. The main source of free radicals responsible for oxidative stress is mitochondrial respiration. The deleterious effects of ROS on cellular biomolecules, including DNA, is a well-known phenomenon that can disrupt mitochondrial function and contribute to cellular damage and death, and the subsequent development of various disease processes. In this review, we summarize the most important findings that implicated mitochondrial oxidative stress in a wide variety of pathologies from Alzheimer disease (AD) to autoimmune type 1 diabetes. This review also discusses attempts to affect oxidative stress as a therapeutic avenue.     

Lupeol Treatment Attenuates Activation of Glial Cells and Oxidative-Stress-Mediated Neuropathology in Mouse Model of Traumatic Brain Injury

Traumatic brain injury (TBI) signifies a major cause of death and disability. TBI causes central nervous system (CNS) damage under a variety of mechanisms, including protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Astrocytes and microglia, cells of the CNS, are considered the key players in initiating an inflammatory response after injury. Several evidence suggests that activation of astrocytes/microglia and ROS/LPO have the potential to cause more harmful effects in the pathological processes following traumatic brain injury (TBI). Previous studies have established that lupeol provides neuroprotection through modulation of inflammation, oxidative stress, and apoptosis in Aβ and LPS model and neurodegenerative disease. However, the effects of lupeol on apoptosis caused by inflammation and oxidative stress in TBI have not yet been investigated. Therefore, we explored the role of Lupeol on antiapoptosis, anti-inflammatory, and antioxidative stress and its potential mechanism following TBI. In these experiments, adult male mice were randomly divided into four groups: control, TBI, TBI+ Lupeol, and Sham group. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of lupeol against neuroinflammation, oxidative stress, and apoptosis. Lupeol treatment reversed TBI-induced behavioral and memory disturbances. Lupeol attenuated TBI-induced generation of reactive oxygen species/lipid per oxidation (ROS/LPO) and improved the antioxidant protein level, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1) in the mouse brain. Similarly, our results indicated that lupeol treatment inhibited glial cell activation, p-NF-κB, and downstream signaling molecules, such as TNF-α, COX-2, and IL-1β, in the mouse cortex and hippocampus. Moreover, lupeol treatment also inhibited mitochondrial apoptotic signaling molecules, such as caspase-3, Bax, cytochrome-C, and reversed deregulated Bcl2 in TBI-treated mice. Overall, our study demonstrated that lupeol inhibits the activation of astrocytes/microglia and ROS/LPO that lead to oxidative stress, neuroinflammation, and apoptosis followed by TBI.     

DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H₂O₂-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H₂O₂ and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl₄ and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy.     

Mitochondria: A Therapeutic Target for Parkinson’s Disease?

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The exact causes of neuronal damage are unknown, but mounting evidence indicates that mitochondrial-mediated pathways contribute to the underlying mechanisms of dopaminergic neuronal cell death both in PD patients and in PD animal models. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission. Defects in either fusion or fission, leading to mitochondrial fragmentation, limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death. Thus, the regulation of mitochondrial dynamics processes, such as fusion, fission and mitophagy, represents important mechanisms controlling neuronal cell fate. In this review, we summarize some of the recent evidence supporting that impairment of mitochondrial dynamics, mitophagy and mitochondrial import occurs in cellular and animal PD models and disruption of these processes is a contributing mechanism to cell death in dopaminergic neurons. We also summarize mitochondria-targeting therapeutics in models of PD, proposing that modulation of mitochondrial impairment might be beneficial for drug development toward treatment of PD.     

Mitochondrial Genome Editing to Treat Human Osteoarthritis—A Narrative Review

Osteoarthritis (OA) is a severe, common chronic orthopaedic disorder characterised by a degradation of the articular cartilage with an incidence that increases over years. Despite the availability of various clinical options, none can stop the irreversible progression of the disease to definitely cure OA. Various mutations have been evidenced in the mitochondrial DNA (mtDNA) of cartilage cells (chondrocytes) in OA, leading to a dysfunction of the mitochondrial oxidative phosphorylation processes that significantly contributes to OA cartilage degeneration. The mitochondrial genome, therefore, represents a central, attractive target for therapy in OA, especially using genome editing procedures. In this narrative review article, we present and discuss the current advances and breakthroughs in mitochondrial genome editing as a potential, novel treatment to overcome mtDNA-related disorders such as OA. While still in its infancy and despite a number of challenges that need to be addressed (barriers to effective and site-specific mtDNA editing and repair), such a strategy has strong value to treat human OA in the future, especially using the groundbreaking clustered regularly interspaced short palindromic repeats (CRIPSR)/CRISPR-associated 9 (CRISPR/Cas9) technology and mitochondrial transplantation approaches.