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Results for “Mitochondrial dysfunction”

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PubMed1983

Decrease in mitochondrial levels of adenine nucleotides and concomitant mitochondrial dysfunction in ischemic rat liver.

The process of mitochondrial dysfunction in ischemic rat liver was studied. A close correlation was found between decrease in the mitochondrial adenine nucleotide content and deterioration of oxidative phosphorylation capacity. The level of total adenine nucleotides, which was 15--20 nmol/mg protein in mitochondria isolated from normal liver, fell to 1--2 nmol/mg protein with concomitant loss of oxidative phosphorylation capacity after anoxic incubation in vitro or in vivo for 120 min. However, neither the permeability barrier to adenine nucleotides nor matrix enzymes were affected under these conditions. The loss of adenine nucleotides was ascribed to degradation of AMP to adenosine and then leakage of the latter. Conventional procedures for maintenance of oxidative phosphorylation capacity of isolated mitochondria, preservation in the cold and addition of ATP or a respiratory substrate under aerobic conditions, were very effective in maintaining the intramitochondrial levels of adenine nucleotides. Of the three species of adenine nucleotides, only AMP was ineffective in maintaining mitochondrial function; mitochondria containing more than 5 nmol of ATP plus ADP/mg protein exhibited normal activity of oxidative phosphorylation, but with less than 2 nmol they showed no activity.

Adenine Nucleotides↗

PubMed2026

Non-coding RNAs and Mitochondrial Dysfunction in Alzheimer's Disease: A Systematic Review.

Alzheimer's disease (AD) is responsible for 70% of dementia cases worldwide, with tau hyperphosphorylation and amyloid-β plaque accumulation representing its core pathological hallmarks. Genetic predisposition, oxidative stress, and neuroinflammation contribute to disease onset and progression. Non-coding ribonucleic acids (ncRNAs) are a class of RNAs which control gene expression and whose dysregulation in AD patients has been linked to amyloid production, neuroinflammation, and mitochondrial dysfunction, which ranges from impaired energy metabolism to disrupted mitochondrial biogenesis and dynamics. Our descriptive systematic review surveyed the involvement of ncRNAs in mitochondrial dysfunction in AD across experimental and clinical literature. We identified multiple microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) that directly regulate mitophagy, mitochondrial biogenesis, mitochondrial autophagic, and apoptotic pathways, mitochondrial dynamics, and protein import mechanisms in AD models. Among the most important candidates demonstrating clinical dysregulation, miR-140 and lncRNA NEAT1 regulate mitophagy, while miR-9, miR-34a, miR-146a, miR-155, and miR-485 are implicated in mitochondrial biogenesis and miR-204 in mitochondrial autophagy. LncRNA BDNF-AS, miR-148a-3p, miR-21-5p, and miR-103a-3p emerged as regulators of the mitochondrial apoptosis pathway with confirmed clinical dysregulation. Multiple ncRNAs control mitochondrial dynamics, of which miR-195, miR-124, and miR-455-3p have also been studied in AD patients. Additionally, several ncRNAs were found to indirectly regulate mitochondrial fission, autophagy, and apoptosis, although the underlying mechanisms require further characterization. Thus, while ncRNA-centered AD research is in its early stages, current mechanistic and translational evidence supports mitochondrially relevant ncRNAs as promising candidates for biomarker and therapeutic development.

Alzheimer Disease↗

PubMed1982

On the mechanism of ischemia-induced mitochondrial dysfunction.

This study was designed to clarify the mechanism of ischemia-induced mitochondrial dysfunction. Anesthetized 24 dogs were divided into 4 groups, which were premedicated with saline for the controls, lipid emulsion 1 ml/kg, DL-carnitine 300 mg/kg or DL-propionylcarnitine 100 mg/kg. Myocardial mitochondria were prepared from both ischemic and non-ischemic areas after 30 min of coronary ligation and their functions, the levels of acyl-CoA and free L-carnitine were measured. In the control group, acyl-CoA level in ischemic mitochondria increased significantly compared with that in non-ischemic mitochondria. Administration of lipid emulsion further increased acyl-CoA level in ischemic mitochondria, but premedication with carnitine or propionylcarnitine prevented the elevation of acyl-CoA level by increasing free L-carnitine level in mitochondria. Ischemic mitochondrial function was disturbed in the control group and premedication with lipid accelerated the dysfunction, while premedication with carnitine or propionylcarnitine reduced the dysfunction. There was a clear reciprocal correlation (r = -0.98) between acyl-CoA level and mitochondrial function. These results indicate that accumulation of acyl-CoA is one of the important factors in ischemia-induced mitochondrial dysfunction.

Acyl Coenzyme A↗

PubMed2000

Mitochondrial dysfunction in congenital nephrotic syndrome.

The molecular mechanisms maintaining the kidney glomerular filtration barrier remain poorly understood. Recent evidence suggests that mitochondrial dysfunction is a characteristic feature of kidney glomeruli in congenital nephrotic syndrome of the Finnish type (CNF). Here we searched for detailed functional evidence of mitochondrial lesion in CNF kidneys. We used histochemical and immunohistochemical methods, quantitative measurement of mitochondrial DNA, and superoxide production to characterize the mitochondrial function. The results unequivocally show down-regulation of mitochondria-encoded respiratory chain components, whereas the respective nuclearly encoded subunits were close to normal. These results give detailed evidence of distinct mitochondrial dysfunction and of the resulting abnormal production of reactive oxygen species in CNF and suggest a critical role for mitochondria in maintaining the glomerular permeability barrier.

DNA, Mitochondrial↗

PubMed2025

Innovative strategies for mitochondrial dysfunction in myeloproliferative neoplasms a step toward precision medicine.

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells characterized by aberrant proliferation of myeloid lineages, driven primarily by mutations in JAK2, CALR, and myeloproliferative leukemia, leading to constitutive activation of the JAK-STAT pathway. Emerging evidence highlights mitochondrial dysfunction as a key factor in MPN pathogenesis, contributing to increased reactive oxygen species production, mitochondrial DNA mutations, and dysregulated mitochondrial dynamics, which collectively promote clonal expansion and apoptosis resistance. Targeting mitochondrial pathways has gained attention as a therapeutic strategy, with approaches including mitochondria-targeted antioxidants, metabolic inhibitors, and modulation of mitophagy and mitochondrial fission/fusion dynamics. However, challenges such as drug delivery specificity, therapeutic resistance, and off-target effects remain significant. Recent advances in precision medicine, incorporating genomic, transcriptomic, and proteomic profiling, offer a more personalized approach to MPN treatment by tailoring interventions to individual mutation patterns. Additionally, novel therapeutic strategies, including gene editing technologies, RNA-based therapies, and nanoparticle-mediated drug delivery systems, hold promise for overcoming current treatment limitations. The integration of artificial intelligence in drug discovery and biomarker identification further enhances the potential for targeted therapies. Future research should focus on refining these strategies, developing reliable biomarkers for patient stratification, and exploring combination therapies that enhance treatment efficacy while minimizing adverse effects. By addressing mitochondrial dysfunction as an underlying driver of MPNs, these emerging approaches have the potential to improve disease management, extend patient survival, and enhance quality of life. Also, this new approach of precision medicine allows patient stratification and ensures that treatments are formed according to the individual disease biology of each patient, which results in overall better outcomes.

combination drug therapy↗

PubMed1999

Role of mitochondrial dysfunction in calcium signalling alterations in dorsal root ganglion neurons of mice with experimentally-induced diabetes.

The role of mitochondrial dysfunction in alterations of calcium signalling in primary sensory neurons has been studied in mice with streptozotocin-induced and genetically predisposed diabetes mellitus before and after additional treatment with insulin infusions. Cytosolic calcium transients triggered by membrane depolarization were measured using a membrane-permeable form of fluorescent indicator indo-1, and their changes after application of mitochondrial uncoupler carbonyl cyanide m-chlorphenylhydrazone were compared in cells of control and diabetic animals. Considerable prolongation of residual elevation of cytosolic calcium after termination of membrane depolarization was observed in diabetic mice, which was expressed mainly in small-sized (nociceptive) neurons. This correlated with the level of hyperglycemia, which was maximal in cells from streptozotocin-treated mice. Insulin partly reversed these changes. Carbonyl cyanide m-chlorophenylhydrazone application to neurons of control mice enlarged the peak of calcium transients and decreased residual calcium elevations, indicating that mitochondria in physiological conditions participate in shaping of these transients by diminishing their peak due to rapid uptake of calcium ions and by prolonging them due to subsequent slow calcium release back into the cytosol. Depression of the calcium accumulating function of mitochondria by carbonyl cyanide m-chlorophenylhydrazone eliminated these changes. The prolonged residual elevation of cytosolic calcium characteristic for neurons of diabetic animals was also eliminated by carbonyl cyanide m-chlorophenylhydrazone, confirming the suggestion that such elevation is determined mainly by mitochondrial dysfunction, the latter being dependent on the level of hyperglycemia. Predominant expression of such changes in small-sized neurons can be explained by the absence in them of effective calcium-buffering by the endoplasmic reticulum. Possible role of the described calcium signalling changes in the origin of neuropathic syndromes is discussed.

Animals↗

PubMed1997

Movement disorders and mitochondrial dysfunction.

Primary defects of mitochondrial DNA leading to respiratory chain dysfunction have been described in association with dystonia, chorea and parkinsonism. Myoclonus remains the commonest movement disorder associated with such defects. The genetic basis of Leigh's syndrome, which is frequently associated with movement disorders, may be mitochondrial or nuclear. Respiratory chain dysfunction has been identified in Huntington's disease in addition to Parkinson's disease, but the cause and relationship of this dysfunction to the pathogenesis of these common disorders is not yet determined.

Chorea↗

PubMed2003

Cyanide enhancement of dopamine-induced apoptosis in mesencephalic cells involves mitochondrial dysfunction and oxidative stress.

Dopamine (DA)-induced neurotoxicity is potentiated when cellular metabolism is compromised. Since cyanide is a neurotoxin that produces mitochondrial dysfunction and stimulates intracellular generation of reactive oxygen species (ROS), KCN was used to study DA-induced apoptosis in primary cultured mesencephalon cells. Treatment of neurons with DA (300 microM) for 24h produced apoptosis as determined by TUNEL staining, DNA fragmentation and increased caspase activity. Pretreatment with KCN (100 microM) 30min prior to DA increased the number of cells undergoing apoptosis. When added to the cells alone, this concentration of KCN did not induce apoptosis. DA stimulated intracellular generation of ROS, and treatment with KCN enhanced ROS generation. Treatment of cells with glutathione or uric acid (antioxidants/scavengers) attenuated both the increase in ROS generation and the apoptosis, demonstrating that ROS are initiators of the cytotoxicity. Studies on the sequence of events mediating the response showed that DA-induced depolarization of the mitochondrial membrane was dependent on ROS generation and KCN enhanced this action of DA. Following changes in mitochondrial membrane potential, cytochrome c was released from mitochondria, leading to caspase activation and eventually cell death. These results demonstrate that oxidative stress and mitochondrial dysfunction are initiators of DA-induced apoptosis. Subsequent cytochrome c release activates the caspase effector component of apoptosis. Cyanide potentiates the neurotoxicity of DA by enhancing the generation of ROS and impairing mitochondrial function.

Animals↗

PubMed2004

Mitochondrial dysfunction and oxidative damage in Alzheimer's and Parkinson's diseases and coenzyme Q10 as a potential treatment.

There is substantial evidence that mitochondrial dysfunction and oxidative damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and oxidative damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as oxidative damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases.

Alzheimer Disease↗

PubMed2006

Mitochondrial dysfunction and ultrastructural damage in the hippocampus of pilocarpine-induced epileptic rat.

Mitochondrial dysfunction has been implicated as a contributing factor in epileptic seizures. Present studies were carried out to decipher seizure-dependent changes in mitochondrial function and ultrastructure in the chronic condition of temporal lobe epilepsy (TLE) induced by pilocarpine in rat hippocampus. Enzyme assay revealed significant depression of the activity of mitochondrial- and nuclear-encoded cytochrome oxidase (COX). Conversely, the activity of nuclear-encoded succinate dehydrogenase (SDH) remained unchanged. Discernible mitochondrial ultrastructural damage, varying from swelling to disruption of membrane, was observed in the hippocampus. Quantitative real-time PCR and Western blotting showed the expression of mitochondrial-encoded COX subunit III (COXIII) dropped significantly during the chronic seizure activity; the corresponding expression of COX subunit IV (COXIV) displayed no significant change. Most likely, our results suggest that dysfunction of mitochondrial COX respiratory enzyme and mitochondrial ultrastructural damage in the hippocampus are associated with prolonged seizure during experimental TLE and mitochondria are more vulnerable to epilepsy.

Animal Diseases↗

PubMed2002

Infantile leukoencephalopathy owing to mitochondrial enzyme dysfunction.

Mitochondrial disease is classically associated with deep gray-matter lesions. When white matter is involved, the lesions are typically subcortical and overshadowed by more significant disease in the gray matter. We report six infants in five families who developed neurodegenerative diseases characterized primarily by abnormalities in deep white-matter structures such as the periventricular region, internal capsule, and corpus callosum. Five patients had impairments of mitochondrial enzymes, including a pre-electron transport chain defect and defects in respiratory chain complexes I, III, and IV (cytochrome-c oxidase). One patient, the sibling of one of the others, was diagnosed clinically with complex III deficiency. These six patients, along with others in the literature, appear to represent a distinct syndrome of mitochondrial infantile leukoencephalopathy. Our observations suggest that infants with leukoencephalopathies, especially leukodystrophies, who do not have one of the more common causes of white-matter disease should be evaluated for mitochondrial dysfunction.

Corpus Callosum↗

PubMed2003

Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.

Adenosine Monophosphate↗

PubMed2006

Clinical implications of mitochondrial dysfunction.

Mitochondria produce metabolic energy, serve as biosensors for oxidative stress, and eventually become effector organelles for cell death through apoptosis. The extent to which these manifold mitochondrial functions are altered by previously unrecognized actions of anesthetic agents seems to explain and link a wide variety of perioperative phenomena that are currently of interest to anesthesiologists from both a clinical and a scientific perspective. In addition, many surgical patients may be at increased perioperative risk because of inherited or acquired mitochondrial dysfunction leading to increased oxidative stress. This review summarizes the essential aspects of the bioenergetic process, presents current knowledge regarding the effects of anesthetics on mitochondrial function and the extent to which mitochondrial state determines anesthetic requirement and potential anesthetic toxicity, and considers some of the many implications that our knowledge of mitochondrial dysfunction poses for anesthetic management and perioperative medicine.

Aged↗

PubMed2006

Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin.

Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration, mainly at the level of complex I and III, is an important source of ROS generation and hence a potential contributor of cardiac reperfusion injury. Appropriate antioxidant strategies could be particularly useful to limit this ROS generation and associated mitochondrial dysfunction. Melatonin has been shown to effectively protect against ischemic-reperfusion myocardial damage. The mechanism by which melatonin exerts this cardioprotective effect is not well established. In the present study we examined the effects of melatonin on various parameters of mitochondrial bioenergetics in a Langerdoff isolated perfused rat heart model. After isolation of mitochondria from control, ischemic-reperfused and melatonin-treated ischemic-reperfused rat heart, various bioenergetic parameters were evaluated such as rates of mitochondrial oxygen consumption, complex I and complex III activity, H2O2 production as well as the degree of lipid peroxidation, cardiolipin content, and cardiolipin oxidation. We found that reperfusion significantly altered all these mitochondrial parameters, while melatonin treatment had strong protective effect attenuating these alterations. This effect appears to be due, at least in part, to the preservation, by ROS attack, of the content and integrity of cardiolipin molecules which play a pivotal role in mitochondrial bioenergetics. Protection of mitochondrial dysfunction was associated with an improvement of post-ischemic hemodynamic function of the heart. Melatonin had also strong protective effect against oxidative alterations to complex I and III as well as to cardiolipin in isolated mitochondria.

Animals↗

PubMed2001

Biomarkers of 3-nitropropionic acid (3-NPA)-induced mitochondrial dysfunction as indicators of neuroprotection.

In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3-Nitropropionic acid (3-NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme important for mitochondrial energy production. We have been studying biomarkers of 3-NPA exposure in the expectation that such markers may be useful in the screening process to identify neuroprotective agents against neurotoxicity produced by mitochondrial energy dysfunction. Animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity and measurement of immediate postmortem rectal temperature. 3-NPA-treated rats experienced progressive hypothermia that reached a loss of 3 degrees C or more in core body temperature by three hours after dosing. The optical density of the SDH stain in brain was reduced, following a similar time course, most prominently in the cerebellum and least sharply in the thalamus. Some rats were given injections of L-carnitine (an enhancer of fatty acid transport) either alone, or as a pretreatment prior to a dose of 3-NPA. Although L-carnitine deficiency by itself can produce mitochondrial dysfunction, pretreatment with L-carnitine was of limited efficacy at overcoming the effects of 3-NPA on either body temperature or quantitative SDH histochemistry. Body temperature and SDH histochemistry may be useful biomarkers for evaluating the efficacy of neuroprotective agents against lower doses of 3-NPA, against other pharmacological models of mitochondrial dysfunction, or even against genetic mitochondrial diseases.

Animals↗

PubMed1999

Mitochondrial dysfunction in Parkinson's disease.

The cause of Parkinson's disease (PD) is unknown, but reduced activity of complex I of the electron-transport chain has been implicated in the pathogenesis of both mitochondrial permeability transition pore-induced Parkinsonism and idiopathic PD. We developed a novel model of PD in which chronic, systemic infusion of rotenone, a complex-I inhibitor, selectively kills dopaminergic nerve terminals and causes retrograde degeneration of substantia nigra neurons over a period of months. The distribution of dopaminergic pathology replicates that seen in PD, and the slow time course of neurodegeneration mimics PD more accurately than current models. Our model should enhance our understanding of neurodegeneration in PD. Metabolic impairment depletes ATP, depresses Na+/K(+)-ATPase activity, and causes graded neuronal depolarization. This relieves the voltage-dependent Mg2+ block of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, which is highly permeable to Ca2+. Consequently, innocuous levels of glutamate become lethal via secondary excitotoxicity. Mitochondrial impairment also disrupts cellular Ca2+ homoeostasis. Moreover, the facilitation of NMDA-receptor function leads to further mitochondrial dysfunction. To a large part, this occurs because Ca2+ entering neurons through NMDA receptors has 'privileged' access to mitochondria, where it causes free-radical production and mitochondrial depolarization. Thus there may be a feed-forward cycle wherein mitochondrial dysfunction causes NMDA-receptor activation, which leads to further mitochondrial impairment. In this scenario, NMDA-receptor antagonists may be neuroprotective.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

S-Allylcysteine prevents the rat from 3-nitropropionic acid-induced hyperactivity, early markers of oxidative stress and mitochondrial dysfunction.

We investigated the effects of S-allylcysteine (SAC) on early behavioral alterations, striatal changes in superoxide dismutase (SOD) activity, lipid peroxidation (LP) and mitochondrial dysfunction induced by the systemic infusion of 3-nitropropionic acid (3-NPA) to rats. SAC (300 mg/kg, i.p.), given to animals 30 min before 3-NPA (30 mg/kg, i.p.), prevented the hyperkinetic pattern evoked by the toxin. In addition, 3-NPA alone produced decreased activities of manganese- (Mn-SOD) and copper/zinc-dependent superoxide dismutase (Cu,Zn-SOD), increased LP (evaluated as the formation of lipid fluorescent products) and produced mitochondrial dysfunction in the striatum (measured as decreased 3-(3,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction). In contrast, pretreatment of 3-NPA-injected rats with SAC resulted in a significant prevention of all these markers. Our findings suggest that the protective actions of SAC are related with its antioxidant properties, which in turn may be accounting for the preservation of SOD activity and primary mitochondrial tasks.

Akathisia, Drug-Induced↗

PubMed2007

The water extract of Omija protects H9c2 cardiomyoblast cells from hydrogen peroxide through prevention of mitochondrial dysfunction and activation of caspases pathway.

The water extract of Omija (Omija) has been used traditionally in the treatment of ischemic damage of the heart and brain tissues. However, little is known about the mechanism by which it rescues myocardial cells from oxidative stress. This study was designed to investigate the protective mechanisms of Omija on H(2)O(2)-induced cytotoxicity in H9c2 cardiomyoblast cells. Treatment with H(2)O(2) resulted in the death of H9c2 cells, characterized by apparent apoptotic features, including fragmentation of the nucleus and an increase in the sub-G(0)/G(1) fraction of the cell cycle. However, Omija markedly suppressed the apoptotic characteristics of H9c2 cells induced by H(2)O(2). In addition, Omija suppressed the features of mitochondrial dysfunction, including changes in the mitochondrial membrane potential and cytosolic release of cytochrome c in H(2)O(2)-treated cells. Treatment with Omija further inhibited the catalytic activation of caspase-9 and caspase-3 and induction of Fas by H(2)O(2). Taken together, these data indicate that the water extract of Omija protects H9c2 cardiomyoblast cells from oxidative stress of H(2)O(2) through inhibition of mitochondrial dysfunction and activation of intrinsic caspase cascades, including caspase-3 and caspase-9.

Antioxidants↗