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Results for “Mitochondria dysfunction”

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At least 919 records · Page 51Linked to original sources

PubMed1996

Dose-dependent increase in sensitivity to calcium-induced mitochondrial dysfunction and cardiomyocyte cell injury by doxorubicin.

We previously reported the induction of calcium-dependent calcium release and depolarization of membrane potential of cardiac mitochondria from rats treated chronically (13 weeks) with doxorubicin. The fact that this was inhibited by cyclosporine A and ruthenium red suggests induction of the mitochondrial permeability transition and calcium cycling. The objective of this investigation was to characterize the cumulative dose-dependent interference with mitochondrial calcium transport by doxorubicin and to assess whether alteration of mitochondrial calcium regulation is manifested as an increased sensitivity to calcium-induced injury to cardiomyocytes isolated from rats exposed in vivo. Mitochondria or cardiomyocytes were isolated from rats treated with 2 mg/kg/week doxorubicin s.c. for 1-9 weeks. Mitochondria isolated from hearts of doxorubicin-treated rats exhibited a dose-dependent increase in sensitivity to calcium-induced calcium release and membrane depolarization, both of which were inhibited by cyclosporine A. Cardiomyocytes isolated from rats treated for 6 weeks with doxorubicin expressed an increased sensitivity to calcium-induced cell killing. The calcium intolerance was prevented by adding either cyclosporine A or ruthenium red to block mitochondrial calcium cycling. These data demonstrate that doxorubicin treatment in vivo causes: (1) a dose-dependent interference with mitochondrial calcium transport and calcium-dependent regulation of membrane potential indicative of induction of the mitochondrial permeability transition, and (2) an increased sensitivity to calcium-induced loss of cell viability. The fact that blocking mitochondrial calcium cycling protected cardiomyocytes from the calcium intolerance suggests that altered regulation of mitochondrial calcium transport may be a critical event in doxorubicin-induced cardiomyopathy.

Animals↗

PubMed2006

Beta-amyloid precursor protein is a direct cleavage target of HtrA2 serine protease. Implications for the physiological function of HtrA2 in the mitochondria.

The processing and metabolism of amyloid precursor protein (APP) is a major interest in Alzheimer disease (AD) research, because not only amyloid beta (Abeta) peptide, but also cellular or mitochondrial APP are intimately involved in cellular dysfunction and AD pathogenesis. Here we demonstrate that APP is directly and efficiently cleaved by the HtrA2 serine protease in vitro and in vivo. Using several APP mutants and N-terminal amino acid sequencing, we identified that the HtrA2-mediated APP cleavage product is the C161 fragment encompassing amino acids 535-695 of APP695. The immunofluorescence and subcellular fractionation studies indicate that APP is partly colocalized with HtrA2 in the mitochondria where HtrA2 can cleave APP under normal conditions. The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2. Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced. These results show that the protease activity of HtrA2 is essential for the production of C161 and that processing of APP into C161 is a natural event occurring under normal physiological conditions. Our study suggests that the direct cleavage of mitochondrial APP by HtrA2 may prevent mitochondrial dysfunction caused by accumulation of APP and that the regulation of HtrA2 protease activity may be a therapeutic target in AD.

Amyloid beta-Protein Precursor↗

PubMed2005

Involvement of mitochondria in myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis: a case report.

We report a 57-year-old male with myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis without evidence of thymoma. He showed prominent muscle wasting and weakness in the four extremities and trunk in addition to swallowing disturbance. He showed intolerance to exercise on a bicycle ergometer, and muscle biopsy specimens demonstrated ragged-red fibers. An anti-acetylcholine receptor (AChR) antibody was detected in his serum but no anti-mitochondrial M2 component antibody was found. In contrast, results of immunohistochemical study indicated that his serum sample reacted to muscle mitochondria as well as AChR. These results indicate the presence of an unidentified anti-mitochondrial antibody that may be involved in the development of mitochondrial dysfunction in skeletal muscle of the present patient.

Arthritis, Rheumatoid↗

PubMed2000

Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction.

We hypothesized that diabetic sensory neuropathy is associated with activation of apoptosis and concomitant mitochondrial dysfunction. Studies were performed in excised intact and acutely dissociated dorsal root ganglion (DRG) neurons from control and streptozotocin-induced diabetic rats with decreased peripheral nerve conduction velocities (NCV). Apoptosis was increased in acutely dissociated DRG neurons from 3- to 6-week-old diabetic rats. Basal mitochondrial membrane potential (deltapsi) was significantly more positive in DRG neurons from diabetic rats. Depolarization with glutamate resulted in significantly more positive deltapsi and delayed recovery of deltapsi in neurons from diabetic rats. Restoration of euglycemia for 2 weeks with insulin implants normalized NCV, deltapsi, and apoptosis. Intact and acutely dissociated neurons from diabetic rats demonstrated decreased Bcl-2 levels and translocation of cytochrome C from the mitochondria to the cytoplasm. Neither levels of Bax nor levels of Bcl-XL were altered in diabetic neuropathy. Apoptosis associated with mitochondrial dysfunction may contribute to the pathogenesis of diabetic sensory neuropathy.

Animals↗

PubMed1994

Impairment of mitochondrial oxidative phosphorylation in the brain of aged mice.

To elucidate the role of mitochondrial oxidative phosphorylation in neuronal aging, we have studied the activity of the respiratory complexes in the brain of young, adult and old mice. In synaptic mitochondria, we found a significant decrease in complexes IV (29%, P < 0.001) and V (21%, P < 0.01) in old as compared with adult mice. Nonsynaptic mitochondria also showed a senescent decrease in complexes I (15%, P < 0.01), II + III (34%, P < 0.01) and IV (17%, P < 0.01) activities. These findings suggest a dysfunction in mitochondrial oxidative phosphorylation in brain aging.

Aerobiosis↗

PubMed1995

Pathogenetic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas.

Myoclonus epilepsy and ragged-red fibers syndrome (MERRF) is caused by a heteroplasmic mutation at nucleotide 8344 (A8344G) of the tRNA(Lys) gene of mitochondrial DNA (mtDNA). This mutation impairs mitochondrial protein synthesis and causes a respiratory chain dysfunction. The risk for transmission of the A8344G mutation from mother to child is dependent on the levels of mutated mtDNA in the mother and above a threshold level of 35-40% the mutation is transmitted to all children. The progression of symptoms in MERRF can be explained by a gene dosage effect with accumulation over time of mutated mtDNA. High levels of mutated mtDNA, ultrastructurally abnormal mitochondria, and a clonal deletion on chromosome 6 are found in lipomas associated with MERRF. These findings indicate that there is a respiratory chain dysfunction in the lipomas and that lipomas may be a manifestation of the A8344G mutation.

Child↗

PubMedDate not supplied

Relationship between regional myocardial blood flow and mitochondrial function.

The purpose of this study was to clarify the relationship between myocardial mitochondrial dysfunction and the degree plus duration of restricted coronary blood flow. 135 anesthetized and open-chest dogs were divided into 3 groups according to coronary occlusion time: 10, 20, and 60 min. Regional myocardial blood flow (MBF) was determined in both ischemic and nonischemic areas before and during coronary occlusion using the hydrogen gas clearance method. Myocardial mitochondria were prepared from each area in which MBF was determined after 10, 20, or 60 min of coronary ligation, and their respiratory control index (RCI), ADP/O, and rate of oxygen consumption in state III O2 (St. III O2) were measured. The MBF measured in 135 dogs before coronary ligation was 103 +/- 25 ml/min/100 g (mean +/- SD) for the area to be rendered ischemic and 101 +/- 24 ml/min/100 g for the control area. The MBF in the ischemic area did not cease completely following coronary ligation, and the distribution of MBF showed variations which seemed attributable to individual differences. In the 10-min group, no index of mitochondrial function of the ischemic area differed from that of the nonischemic area at any level of MBF. When MBF was less than 20 ml/min/100 g, RCI of mitochondria from the ischemic area was significantly lower than that from the nonischemic area, in the 20- and 60-min groups. When MBF was less than 20 ml/min/100 g, St. III O2 of mitochondria from the ischemic area significantly decreased compared with that from the nonischemic area, in the 20-min group. In the 60-min group, MBF less than 30 ml/min/100 g, St. III O2 of mitochondria from the ischemic area was likewise significantly decreased. Moreover, with MBF below 20 ml/min/100 g, both RCI and St. III O2 of mitochondria from the ischemic area were significantly lower in the 60-min group than in the 20-min group. These results indicate that ischemia-induced mitochondrial dysfunction depends on the degree of decrease in the blood flow of the area involved as well as on the duration of ischemia, and the blood flow that is critical for survival, based on mitochondrial function, is approximately 20 ml/min/100 g, i.e., a reduction to 20% of normal value.

Animals↗

PubMed2003

Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death.

The function of the nervous system relies upon synaptic transmission, a process in which a neurotransmitter released from pre-synaptic terminals of one neuron (in response to membrane depolarization and calcium influx) activates post-synaptic receptors on dendrites of another neuron. Synapses are subjected to repeated bouts of oxidative and metabolic stress as the result of changing ion gradients and ATP usage. Mitochondria play central roles in meeting the demands of synapses for ATP and in regulating calcium homeostasis, and mitochondrial dysfunction can cause dysfunction and degeneration of synapses, and can trigger cell death. We have identified two types of mitochondrial proteins that serve the function of protecting synapses and neurons against dysfunction and death. Mitochondrial ATP-sensitive potassium (MitoKATP) channels modulate inner membrane potential and oxyradical production; mitochondrial potassium fluxes can affect cytochrome c release and caspase activation and may determine whether neurons live or die in experimental models of stroke and Alzheimer's disease. Uncoupling proteins (UCPs) are a family of mitochondrial membrane proteins that uncouple electron transport from ATP production by transporting protons across the inner membrane. Neurons express at least three UCPs including the widely expressed UCP-2 and the neuron-specific UCP-4 and UCP-5 (BMCP-1). We have found that UCP-4 protects neurons against apoptosis by a mechanism involving suppression of oxyradical production and stabilization of cellular calcium homeostasis. The expression of UCP-4 is itself regulated by changes in energy metabolism. In addition to their roles in neuronal cell survival and death, MitoKATP channels and UCPs may play roles in regulating neuronal differentiation during development and synaptic plasticity in the adult.

Apoptosis↗

PubMed2006

The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis.

A truncated form of the Huntington's disease (HD) protein that contains the polyglutamine repeat, Httex1p, causes HD-like phenotypes in multiple model organisms. Molecular signatures of pathogenesis appear to involve distinct domains within this polypeptide. We studied the contribution of each domain, singly or in combination, to sub-cellular localization, aggregation and intracellular Ca2+ ([Ca2+]i) dynamics in cells. We demonstrate that sub-cellular localization is most strongly influenced by the first 17 amino acids, with this sequence critically controlling Httex1p mitochondrial localization and also promoting association with the endoplasmic reticulum (ER) and Golgi. This domain also enhances the formation of visible aggregates and together with the expanded polyQ repeat acutely disrupts [Ca2+]i levels in glutamate-challenged PC12 cells. Isolated cortical mitochondria incubated with Httex1p resulted in uncoupling and depolarization of these organelles, further supporting the idea that Httex1p-dependent mitochondrial dysfunction could be instrumental in promoting acute Ca2+ dyshomeostasis. Interestingly, neither mitochondrial nor ER associations seem to be required to promote long-term [Ca2+]i dyshomeostasis.

Animals↗

PubMed1996

Creation and characterization of mitochondrial DNA-depleted cell lines with "neuronal-like" properties.

Mitochondrial dysfunction and attendant bioenergetic defects are increasingly recognized as playing an important role in neurodegenerative disorders. The increased attention on mitochondrial involvement points to the need for developing cell lines that have neuron-like characteristics for the genetic analysis and modeling of these diseases. We describe the creation of respiratory-deficient SH-SY5Y neuroblastoma cell lines (rho zero 64/5) by selectively depleting mitochondrial DNA through prolonged exposure to ethidium bromide. Oxygen consumption in these cells and activities of the electron transport chain enzyme complexes I and IV that contain subunits encoded by the mitochondrial genome are eliminated. In contrast, the function of complex II, a nuclear-encoded electron transport chain component, is largely intact in these cells. The rho zero 64/5 cells retain the ability to differentiate into cells with neuron-like phenotypes following treatment with phorbol ester or retinoic acid. Normal respiratory function is recovered by repopulation of rho zero 64/5 cells with exogenous human platelet mitochondria. The rho zero 64/5 cell line serves as a valuable model for the study of neurologic diseases suspected of involving mitochondrial dysfunction.

Blood Platelets↗

PubMed2004

The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head.

AIM: To study the normal distributions of mitochondria and voltage gated Na+ channels in the human optic nerve head in order to gain insight into the potential mechanisms of optic nerve dysfunction seen in the inherited optic neuropathies. METHODS: Five fresh frozen human optic nerves were studied. Longitudinally orientated, serial cryosections of optic nerve head were cut for mitochondrial enzyme histochemistry and immunolabelling for cytochrome c oxidase (COX) subunits and voltage gated Na+ channel subtypes (Na(v) 1.1, 1.2, 1.3, and 1.6). RESULTS: A high density of voltage gated Na+ channels (subtypes Na(v) 1.1, 1.3, and 1.6) in the unmyelinated, prelaminar, and laminar optic nerve was found. This distribution co-localised both with areas of high COX activity and strong immunolabelling for COX subunits I and IV. CONCLUSIONS: Increased numbers of mitochondria in the prelaminar optic nerve have previously been interpreted as indicating a mechanical hold up of axoplasmic flow at the lamina cribrosa. These results suggest that this increased mitochondrial density serves the higher energy requirements for electrical conduction in unmyelinated axons in the prelaminar and laminar optic nerve and is not a reflection of any mechanical restriction. This could explain why optic neuropathies typically occur in primary inherited mitochondrial diseases such as Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibres (MERRF), and Leigh's syndrome. Secondary mitochondrial dysfunction has also been reported in dominant optic atrophy, Friedreich's ataxia, tobacco alcohol amblyopia, Cuban epidemic optic neuropathy, and chloramphenicol optic neuropathy. These diseases are rare but these findings challenge the traditional theories of optic nerve structure and function and may suggest an alternative approach to the study of commoner optic neuropathies such as glaucoma.

Adult↗

PubMed2005

Synergistic inhibition of respiration in brain mitochondria by nitric oxide and dihydroxyphenylacetic acid (DOPAC). Implications for Parkinson's disease.

The inhibition of mitochondrial respiration by nitric oxide (.NO) at cytochrome c oxidase level has been established as a physiological regulatory mechanism of mitochondrial function. Given, on the one hand, the potential involvement of .NO and dopamine metabolism in mitochondrial dysfunction associated with neurodegeneration and, on the other hand, the reported interaction of .NO with dihydroxyphenylacetic acid (DOPAC), a major mitochondrial-associated dopamine metabolite, we examined the combined effects of .NO and DOPAC on the respiratory chain of isolated rat brain mitochondria. Whereas dopamine or DOPAC induced no measurable effects on the mitochondrial respiration rate, a mixture of .NO with DOPAC inhibited the rate in a way stronger than that exerted by .NO. This effect was noticed with actively respiring (state 3) and resting (state 4) mitochondria. At variance with DOPAC, dopamine failed to potentiate .NO inhibitory effects. The inhibition was dependent on the concentration of both compounds, .NO and DOPAC, and exhibited characteristics similar to those exerted by .NO, namely: it was reversible and dependent on the concentration of oxygen. Analysis of respiratory enzymatic activities demonstrated a selective inhibition at the level of cytochrome c oxidase (complex IV). Insights into the chemical mechanisms underlying the inhibitory effect were inferred from experiments using metmyoglobin (a ligand for .NO and derived species, such as nitroxyl anion) and ferrocyanide (a reductant of .NO, producing nitroxyl anion). Whereas metmyoglobin decreased the inhibition, ferrocyanide potentiated the inhibition. Moreover, a mixture of ferrocyanide with .NO reproduced the effects exerted by the mixture of .NO with DOPAC. The results are consistent with the notion of a reaction of .NO with DOPAC producing a nitric oxide-derived compound(s), which inhibit O2 uptake at the cytochrome oxidase level. Although the mechanism in question remains to be clearly elucidated it is suggested that the .NO/DOPAC-dependent inhibition of cytochrome oxidase may involve nitroxyl anion. The significance of these observations for mitochondrial dysfunction inherent in Parkinson's disease is discussed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2025

Mapping key mitochondrial genes in Alzheimer's disease through human tissue and iPSC derived neurons.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that has become a global health challenge due to an aging world population and no available effective treatment. Mitochondrial dysfunction plays a crucial role in the development of AD due to its critical role in neuronal survival and function. However, the specific mitochondrial genes and pathways involved in AD pathogenesis remain poorly defined. In this study, we incorporated seven AD human postmortem and three AD iPSC-derived neurons (iNs) gene expression datasets to identify mitochondria-related Differentially Expressed Genes (mitoDEGs) between AD and control. The Gene Ontology (GO) analysis is conducted to investigate the AD biological mechanisms, and a random forest model is developed to assess how well the key mitoDEGs differentiate AD and control groups. Through our analysis, we identified fourteen key mitochondria related genes that show significant dysregulation in both postmortem brain tissues and iNs derived from AD patients. These genes have strong connections to oxidative stress, indicating mitochondrial dysfunction plays a crucial role in Alzheimer's disease pathology. Our study identified the key genes and pathways as promising targets for future research and therapeutic interventions, highlighting the importance of mitigating oxidative stress and restoring mitochondrial function in AD.

Humans↗

PubMed2025

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for 1) extracellular matrix structure and metabolism (TM1 subtype), 2) secreted ligand signaling to support Schlemm's canal cells (TM2), and 3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2,491 TM cells). In V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), to enhance mitochondrial function and metabolic resilience, significantly protected Lmx1b mutant mice from IOP elevation.

Journal Article↗

PubMed2003

Mitochondrial-targeted drug and DNA delivery.

The field of mitochondrial research is currently among the fastest growing disciplines in biomedicine. Approximately 12,000 articles on mitochondria have been published since the beginning of the new millennium. What brings mitochondria into the limelight of the scientific community? Since the end of the 1980s, a series of key discoveries has been made that have rekindled the scientific interest in this long-known cell organelle. It has become increasingly evident that mitochondrial dysfunction contributes to a variety of human disorders, ranging from neurodegenerative and neuromuscular diseases, obesity, and diabetes to ischemia-reperfusion injury and cancer. Moreover, since the middle of the 1990s, mitochondria, the "power houses" of the cell, have also become accepted as the cells' "arsenal," reflecting their increasingly acknowledged key role during apoptosis. Based on these recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of mitochondrial medicine" as a new field of biomedical research. Targeting of biologically active molecules to mitochondria in living cells will open avenues for manipulating mitochondrial functions, which may result in the selective protection, repair, or eradication of cells. This review gives a comprehensive overview of current strategies of mitochondrial targeting and their possible therapeutic applications.

Apoptosis↗

PubMed2005

Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD+/-): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.

Aldehyde Dehydrogenase↗

PubMed1999

Apoptosis: a two-edged sword in aging.

Here we summarize briefly what is known about both the positive and negative impacts of apoptosis during aging in mammalian systems and also update an earlier review. It is important to understand both of these impacts to devise useful interventions. Such interventions include both physiological and molecular approaches, including transgenic interventions. The critical roles of the mitochondria in both generating reactive oxygen species, and in initiating apoptosis are recognized, suggesting that maintaining mitochondrial function could be an important therapeutic goal, especially in post-mitotic tissues. In contrast, the ability to eliminate unwanted, damaged and dysfunctional cells through apoptosis has anti-aging implications in mitotic tissues.

Aging↗

PubMed1985

Loss of calmodulin activity in cardiac sarcoplasmic reticulum after ischemia.

Experiments were designed to evaluate whether cardiac ischemia affected the subcellular distribution of calmodulin activity. Major cellular fractions (nuclei, mitochondria, sarcoplasmic reticulum and cytosol) were isolated from globally ischemic hearts by differential centrifugation. Ischemia did not affect calmodulin activity in cell fractions other than sarcoplasmic reticulum, which showed a consistent and complete loss of activity. This site-specific loss of calmodulin activity may be one mechanism by which ischemia induces contractile dysfunction.

Animals↗