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PubMed1997

Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin.

Friedreich's ataxia is due to loss of function mutations in the gene encoding frataxin (FRDA). Frataxin is a protein of unknown function. In situ hybridization analyses revealed that mouse frataxin expression correlates well with the main site of neurodegeneration, but the expression pattern is broader than expected from the pathology of the disease. Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat and heart. We found that mouse and yeast frataxin homologues contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction. Finally, tagging experiments demonstrate that human frataxin co-localizes with a mitochondrial protein. Friedreich's ataxia is therefore a mitochondrial disease caused by a mutation in the nuclear genome.

Amino Acid Sequence↗

PubMed2002

Regulation of apoptotic cell death by cytokines in a human salivary gland cell line: distinct and synergistic mechanisms in apoptosis induced by tumor necrosis factor alpha and interferon gamma.

We examined the mechanisms of apoptosis in a human salivary gland (HSG) cell line induced by tumor necrosis factor (TNF) alpha and interferon (IFN) gamma. DNA fragmentation and the activation of caspase-3 were determined in HSG cells cultured with TNF-alpha or IFN-gamma. Mitochondrial dysfunction also appeared to be involved in the process because a disruption of mitochondrial transmembrane potential with the activation of caspase-9 was demonstrated in TNF-alpha- and IFN-gamma-stimulated HSG cells. Activation of caspase-8 was thought to be essential in TNF-alpha--induced apoptosis of HSG cells; however, the activation of caspase-8 was not involved in IFN-gamma-induced apoptosis of HSG cells. In contrast, Bcl-2 appeared to be an indispensable regulatory molecule in IFN-gamma-induced, but not in TNF-alpha-induced, apoptosis of HSG cells because its expression was inhibited in IFN-gamma-stimulated, but not in TNF-alpha-stimulated, cells. The inhibitory effect of IFN-gamma in Bcl-2 expression was enhanced by coadministration of TNF-alpha and, interestingly, apoptosis of HSG cells, as assessed by DNA fragmentation and the activation of caspase-9 and caspase-3, and disruption of mitochondrial transmembrane potential was also synergistically augmented by TNF-alpha and IFN-gamma. Our results suggest that cytokines expressed in the salivary glands of patients with Sjögren syndrome play an important role in regulating apoptosis of acinar-ductal epithelial cells through distinct and synergistic mechanisms, thereby modulating salivary gland function in patients with Sjögren syndrome.

Apoptosis↗

PubMed1993

Male-sterility induction in transgenic tobacco plants with an unedited atp9 mitochondrial gene from wheat.

Cytoplasmic male sterility in plants is associated with mitochondrial dysfunction. We have proposed that a nuclear-encoded chimeric peptide formed by mitochondrial sequences when imported into the mitochondria may impair organelle function and induce male sterility in plants. A model developed to test this hypothesis is reported here. Assuming that the editing process in higher plant mitochondria reflects a requirement for producing active proteins, we have used edited and unedited coding sequences of wheat ATP synthase subunit 9 (atp9) fused to the coding sequence of a yeast coxIV transit peptide. Transgenic plants containing unedited atp9 exhibited either fertile, semifertile, or male-sterile phenotypes; controls containing edited atp9 or only the selectable marker gave fertile plants. Pollen fertility ranged from 31% to 75% in fertile plants, 10% to 20% in semifertile plants, and < 2% in male-sterile plants. Genetic and molecular data showed that the chimeric plasmid containing the transgene is inherited as a Mendelian trait. The transgenic protein is imported into the mitochondria. The production and frequency of semifertile or male-sterile transgenic plants conform to the proposed hypothesis.

Amino Acid Sequence↗

PubMed2005

Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin.

There is significant evidence that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of Huntington disease. Nonetheless, the specific mitochondrial defects due to the presence of mutant huntingtin have not been fully elucidated. To determine the effects of mutant huntingtin on mitochondrial energy production, a thorough analysis of respiration, ATP production, and functioning of the respiratory complexes was carried out in clonal striatal cells established from Hdh(Q7) (wild-type) and Hdh(Q111) (mutant huntingtin knock-in) mouse embryos. Mitochondrial respiration and ATP production were significantly reduced in the mutant striatal cells compared with the wild-type cells when either glutamate/malate or succinate was used as the substrate. However, mitochondrial respiration was similar in the two cell lines when the artificial electron donor TMPD/ascorbate, which feeds into complex IV, was used as the substrate. The attenuation of mitochondrial respiration and ATP production when either glutamate/malate or succinate was used as the substrate was not due to impairment of the respiratory complexes, because their activities were equivalent in both cell lines. Intriguingly, in the striatum of presymptomatic and pathological grade 1 Huntington disease cases there is also no impairment of mitochondrial complexes I-IV (Guidetti, P., Charles, V., Chen, E. Y., Reddy, P. H., Kordower, J. H., Whetsell, W. O., Jr., Schwarcz, R., and Tagle, D. A. (2001) Exp. Neurol. 169, 340-350). To our knowledge, this is the first comprehensive analysis of the effects of physiological levels of mutant huntingtin on mitochondrial respiratory function within an appropriate cellular context. These findings demonstrate that the presence of mutant huntingtin impairs mitochondrial ATP production through one or more mechanisms that do not directly affect the function of the respiration complexes.

Adenosine Triphosphate↗

PubMed2005

Risperidone-induced psychosis and depression in a child with a mitochondrial disorder.

OBJECTIVE: To our knowledge, this is the first published case report of an adolescent girl with a mitochondrial disorder and depression who displayed both new-onset psychotic and increased mood symptoms during treatment with risperidone. DATA: A 16-year-old girl was treated with risperidone for mood lability and impulsivity at a community hospital. Within days, she developed paranoid ideation, profound psychomotor retardation, increased depression, and fatigue. She was transferred to an inpatient psychiatric hospital, where she was taken off risperidone. Within 48 hours after discontinuation of the medication, she had complete resolution of psychotic symptoms, fatigue, and psychomotor retardation, and her depression improved. CONCLUSIONS: This observation of "on-off" risperidone treatment suggests that risperidone may have worsened both psychiatric and physical manifestations of the mitochondrial disorder in this adolescent. These findings are consistent with recent in vitro literature, which implicate a series of neuroleptic medications with mitochondrial dysfunction. Furthermore, the authors provide diagnostic and treatment options that are available for mitochondrial disorders, which are of interest to child psychiatrists due to the central nervous system manifestations of these disorders.

Adolescent↗

PubMed2003

Silica-induced caspase activation in mouse alveolar macrophages is dependent upon mitochondrial integrity and aspartic proteolysis.

Although silica has been documented to cause apoptotic cell death, the cellular pathways leading to caspase activation have not been extensively investigated. Here we demonstrate in a mouse macrophage cell line (MH-S cells) that alpha-quartz silica exposure (12.5 mug/cm2 to 50 mug/cm2) elicited activation of both caspase 3 and caspase 9, whereas anatase titanium dioxide (TiO2), a non-fibrogenic particle, did not. Silica exposure in vitro also induced apoptosis after 6 h, as measured by the appearance of subdiploid cell fragments in a flow cytometric analysis. Exposure to TiO 2 did not elicit significant apoptosis. Silica-induced apoptosis and caspase 3 activation were, in part, caspase 9 dependent, as determined by their sensitivity to either a general caspase inhibitor (Z-VAD-FMK) or a specific caspase 9 inhibitor (Z-LEHD-FMK). Silica exposure in vitro also elicited significant mitochondrial depolarization after 2 and 6 h of exposure. Cyclosporin A, an inhibitor of the mitochondrial permeability pore, partially decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, suggesting a role for mitochondrial dysfunction in these events. Pepstatin A, an inhibitor of cathepsin D, also decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, whereas leupeptin, an inhibitor of cathepsin B, had no effect. These data suggest that short-term silica exposure in vitro induces both caspase 3 and caspase 9 activity, which appears to participate in apoptosis. Activation of these caspases seems to be dependent, in part, on aspartic proteolysis and loss of mitochondrial integrity.

Animals↗

PubMed2002

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism.

BACKGROUND: Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period. CASE PRESENTATION: We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance. CONCLUSIONS: This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease.

Biomarkers↗

PubMed2005

The alpha-ketoglutarate-dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration.

Damage from oxidative stress and mitochondrial dysfunction occur together in many common neurodegenerative diseases. The enzymes that form the mitochondrial alpha-ketoglutarate- dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. KGDHC activity is reduced in numerous age-related neurodegenerative diseases and is diminished by oxidative stress. In Alzheimer's disease (AD), the reduction correlates highly to diminished mental performance. Thus, research has focused on the mechanisms by which select oxidants reduce KGDHC and the consequences of such a reduction. Diminished KGDHC in cells is associated with apoptosis without changes in the mitochondrial membrane potential. Studies of isolated mitochondria and of animal models suggest that a reduction in KGDHC can predispose to damage by other toxins that promote neurodegeneration. Diminished oxidative metabolism can be plausibly linked to pathological features of neurodegenerative diseases (e.g., reduced mental function, the plaques and tangles in AD). Thus, reductions in KGDHC might be central to the pathophysiology of these diseases. Studies of proteins, cells, animal models, and humans suggest that treatments to diminish, or bypass, the reduction in KGDHC might be beneficial in age-related neurodegenerative disorders.

Animals↗

PubMed1984

Relationship between regional myocardial blood flow and tissue ATP content in acute ischemia.

This study was undertaken to determine the relationships between myocardial mitochondrial function, regional myocardial blood flow (MBF), and tissue ATP content in acute ischemia. Fifty-one anesthetized dogs were used in the tests. MBF was measured by the H2 gas clearance method in order to define the ischemic area, during periods of coronary occlusion of 10, 20, 60, and 90 min. The correlation between MBF and myocardial ATP content in the ischemic area was positive and significant in each group (r = 0.54-0.82). The ATP content in the true ischemic area (where MBF was less than 20 ml/min/100 Gm) decreased significantly even after 10 min of occlusion, but mitochondrial function decreased only after 20 min of coronary occlusion when compared to the nonischemic area. Although ischemia induces mitochondrial dysfunction, a very short period of ischemia did not cause significant disturbance of mitochondrial function. Moreover, in the areas with MBF of 20-40 ml/min/100 Gm, the ATP content began to decrease 60 min after occlusion, whereas 10 or 20 min of occlusion did not reduce the ATP content. These results suggest that normal maintenance of ATP levels depends not only on MBF itself but also on the duration of ischemia plus the degree of damage to mitochondrial function, and that critical blood flow, defined as the minimum flow necessary to maintain the level of myocardial ATP, varies with the duration of ischemia.

Acute Disease↗

PubMed2007

Oxidative damage lipid peroxidation in the kidney of choline-deficient rats.

Phosphatidylcholine is the most abundant phospholipid constituent of cell membranes and choline is a quaternary amine required for phosphatidylcholine synthesis. The impairment of membrane functions is considered as an indication of oxidative damage. In order to kinetically analyze the time course of the pathogenesis of renal necrosis following to choline deficiency in weanling rats, we determined markers of membrane lipid peroxidation (thiobarbituric acid reactive substances; TBARS and hydroperoxide-induced chemiluminescence (BOOH-CL) ) and studied the histopathological damage. Plasma TBARS (t(1/2) = 2.5 days) was an early indicator of systemic oxidative stress, likely involving liver and kidney. The levels of TBARS an BOOH-CL increased by 80% and by 183%, respectively, in kidney homogenates with t(1/2) = 1.5 days and 4 days, respectively. The levels of BOOH-CL were statistically higher in rats fed a choline-deficient diet at day 6, in a mixture of membranes (from plasmatic, smooth and rough endoplasmic reticulum and Golgi), in mitochondrial membranes and in lysosomal membranes. The results indicate that choline deficiency produces oxidative damage in kidney subcellular membranes. Necrosis involved mainly convoluted tubules and appeared with a t(1/2) = 5.5 days. An increase in the production of reactive oxygen species, triggered by NADH overproduction in the mitochondrial dysfunction associated with choline deficiency appears as one of the pathogenic mechanism of mitochondrial and cellular oxidative damage in choline-deficiency.

Animals↗

PubMed1987

[Relation between glutamate and adenine nucleotide levels of heart mitochondria during hypoxia].

The effect of acute respiratory hypoxia in rats on mitochondrial respiration, adenine nucleotides and some amino acids of the heart was studied. The decrease in the total (ATP + ADP + AMP) and exchangeable (ATP + ADP) adenine nucleotide pool of the mitochondria was accompanied by a pronounced loss of state 3 respiration with glutamate plus malate and a slight decrease with succinate plus rothenone. The uncoupled respiration of mitochondria with glutamate and malate was decreased in the same degree as in the absence of 2,4-dinitrophenol. State 4 respiration with substrates of both types was unaffected by hypoxia. These data point to a hypoxia-induced impairment of complex I of the respiratory chain. The decrease of tissue and mitochondrial glutamate was accompanied by the elevation of alanine content in the heart and an increase in intramitochondrial aspartate. The ADP-stimulated respiration of mitochondria was correlated with mitochondrial glutamate and ATP as well as with exchangeable adenine nucleotide pools during hypoxia. The experimental results suggest that mitochondrial dysfunction induced by hypoxia may also be attributed to the low level of mitochondrial glutamate.

Adenine Nucleotides↗

PubMed2026

Shielding the First 24 Postnatal Months of Life: A Proposal for a Prospective Cohort Study of Early-Life Electromagnetic Exposure and Autism Risk.

BACKGROUND: Autism Spectrum Disorder (ASD) involves Mirror Neuron System (MNS) dysfunction, driving core social and imitative impairments. Systemic physiological alterations such as autonomic dysregulation, mitochondrial dysfunction and neuroinflammation are known to impair synchronization and plasticity of neuronal clusters. A less-evident environmental cofactor, coinciding with rising ASD prevalence, is the considerable world-wide increase in electromagnetic radiation (EMR) overall exposure among children. Experimental evidence shows how low-intensity EMR influences cellular processes, via voltage-gated calcium channels (VGCCs), oxidative stress, and mitochondrial metabolism. The Resonant Convergence framework, allow to predict how chronic EMR exposure during the first 24 postnatal months of life can act as a factor in ASD pathogenesis. The best candidate mechanism is chronic Ion Cyclotron Resonance (ICR) detuning the Ca2+-calmodulin pathway, thus disrupting MNS synchronization. METHODS AND ANALYSIS: A prospective observational pilot cohort study (24-month follow-up) proposes to enroll 1000 full-term newborns into two arms: an EMR-reduced cohort (n = 500, rest and sleep-phase Faraday shielding) and a standard exposure cohort (n = 500). Exposure is quantified via radiofrequency (RF)/extremely low frequency(ELF) measurements, proximity analysis, device inventories and wearable dosimetry. The primary endpoint is a continuous neurodevelopmental trajectory score (joint attention, language, electroencephalogram (EEG) mu-rhythm); binary ASD diagnosis (Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R)) is a secondary, exploratory endpoint. Moreover, an optional genomic screening will evaluate gene-environment interactions within extremely low-frequency electromagnetic field (ELF-EMF) vulnerable pathways, including ASD-associated genes upregulated by RF via bromodomain and extraterminal protein (BET)-mediated epigenetic mechanisms. Analyses will employ risk ratios, Fisher's exact tests and logistic regression adjusted for confounders; mixed-effects and Bayesian modeling will evaluate longitudinal outcomes and exposure reduction effects. Given a 2-3% baseline prevalence, approximately 20-30 ASD cases are expected. The study is therefore powered for exploratory signal detection rather than definitive causal inference, providing the critical baseline data required to justify and design future confirmatory trials. Sex-stratified modeling will address the 4:1 male-to-female prevalence ratio. ETHICS AND DISSEMINATION: Ethics committee approval is not yet sought; full protocol review and approval will be obtained prior to the study initiation, in strict accordance with the Declaration of Helsinki. Written parental informed consent will be mandatory for all participants prior to enrollment. Study findings and methodological milestones will be disseminated through peer-reviewed international scientific publications. This protocol provides a structured methodological framework for the first prospective investigation of sleep-phase EMR reduction as a potential modulator of ASD incidence during early neurodevelopment. Results will inform adequately powered confirmatory trials in electromagnetic neurodevelopmental epidemiology.

autism spectrum disorder↗

PubMed2025

Integrated Multiomics Analyses of the Molecular Landscape of Sarcopenia in Alcohol-Related Liver Disease.

BACKGROUND: Skeletal muscle is a major target for ethanol-induced perturbations, leading to sarcopenia in alcohol-related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis-driven experiments, an integrated multiomics-experimental validation approach provides a comprehensive view of these interactions. METHODS: We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol-treated (ET) murine and human-induced pluripotent stem cell-derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol-related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence-associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. RESULTS: Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia-inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, -log(p-value) = 1.5-3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI-V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol-induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). CONCLUSIONS: An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post-mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

Sarcopenia↗

PubMed1999

Kearns-Sayre syndrome: unusual pattern of expression of subunits of the respiratory chain in the cerebellar system.

Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder of oxidative phosphorylation associated with clonally expanded rearrangements of mitochondrial DNA (mtDNA). Mitochondrial dysfunction in the central nervous system of patients with KSS accounts for the neurological manifestations of the disease. To gain further insight into the pathogenesis of neuronal dysfunction in KSS, we used antibodies against mtDNA-encoded and nuclear DNA-encoded subunits of the mitochondrial respiratory chain to study the expression of these proteins in the cerebellar cortex, dentate nucleus, and inferior olivary nucleus from 2 autoptic cases of KSS. Neuropathological examination showed a moderate loss of Purkinje cells and spongiform degeneration of the cerebellar white matter. By using immunohistochemistry, we found a decreased expression of mtDNA-encoded proteins only in neurons of the dentate nucleus. We suggest that mitochondrial abnormalities in the dentate nucleus in conjunction with loss of Purkinje cells and spongiform degeneration of the cerebellar white matter may be important factors in the genesis of the cerebellar dysfunction in KSS.

Cerebellum↗

PubMed1996

Abnormalities in the mitochondrial permeability transition in diabetic rats.

Evidence of mitochondrial dysfunction in diabetes led us to examine whether diabetes altered the nature of the mitochondrial permeability transition. Our data reveal three diabetes-associated abnormalities in PT function: consistently delayed induction with calcium-phosphate, a variable delay with calcium-t-butyl-hydroperoxide (t-BuOOH), and an enhanced magnitude of response. The consistently delayed induction in calcium and phosphate is correlated with serum glucose levels, and is consistent with known changes in calcium uniporter function in diabetics. These data expand our knowledge of diabetes-associated abnormalities in mitochondrial function, represent the first evidence that the PT is altered by chronic disease, and provide potential partial mechanistic explanations for the previously observed resistance of diabetic tissues to ischemia-reperfusion injury and the altered Ca2+ homeostasis in diabetics.

Animals↗

PubMed1993

Protection by Cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts.

Reperfusion following a period of ischemia can salvage the myocardium only if the ischemic episode has not exceeded a certain time limit; beyond this point damage becomes irreversible. A key feature of the transition from reversible to irreversible injury is mitochondrial dysfunction which may involve the opening of a non-specific pore in the mitochondrial inner membrane. Pore opening can be induced in vitro by exposure of isolated mitochondria to high [Ca2+] and Pi. Such pore formation is sensitized by adenine nucleotide depletion and oxidative stress and can be blocked by the immunosuppressant cyclosporin A. Here we show that in isolated perfused rat hearts subjected to 30 min ischemia and 15 min reperfusion, 0.2 microM cyclosporin A restored the ATP/ADP ratio and AMP content (decreased and increased respectively during ischemia) to pre-ischemic values. In separate experiments functional recovery was assessed by monitoring the restoration of left ventricular developed pressure (LVP) during reperfusion after 30, 40 or 45 min ischemia. LVP was substantially improved in the presence of 0.2 microM cyclosporin A but did not return to pre-ischemic levels. The cyclosporin analogues G and H were less effective than cyclosporin A in protecting the heart during reperfusion. This is consistent with their reduced ability to protect isolated mitochondria from damage caused by Ca2+ overload. Surprisingly, reperfusion of hearts with 1 microM cyclosporin A reversed the protective effect seen at 0.2 microM.

Adenine Nucleotides↗

PubMed2006

The important role of taurine in oxidative metabolism.

Several studies have demonstrated that especially high taurine concentrations are found in tissues with high oxidative activity, whereas lower concentrations are found in tissues with primary glycolytic activity. Based on such observations, we have studied if taurine is involved in mitochondrial oxidation. Several pieces of information have demonstrated taurine localisation in the mitochondria. We have developed a general biochemical model with preliminary data demonstrating the important role of taurine as mitochondrial matrix buffer for stabilising the mitochondrial oxidation. The model can have far-reaching perspectives, e.g., explaining the often-suggested anti-oxidative role of taurine, in contrast to the fact that taurine is very difficult to chemically oxidise. By stabilising the environment in the mitochondria, taurine will prevent leakage of the reactive compounds formed in the reactive mitochondrial environment and thus indirectly act as an antioxidant. Consequently, the model represents a new concept for understanding mitochondrial dysfunction by emphasising the importance of taurine for providing sufficient pH buffering in the mitochondrial matrix.

Animals↗

PubMed2005

Caspase-3-dependent protein kinase C delta activity is required for the progression of Ginsenoside-Rh2-induced apoptosis in SK-HEP-1 cells.

Ginsenoside-Rh2 (G-Rh2) has been shown to induce apoptosis in a variety of cell types. In this study, we show that G-Rh2-induced apoptosis is accompanied by the mitochondrial release of cytochrome c and activation of caspase-3 in the human hepatoma cell line, SK-HEP-1. Furthermore, protein kinase C delta (PKCdelta) activity was markedly up-regulated in a lipid activator-independent manner with kinetics similar to those of PKCdelta and PARP cleavages during the apoptotic progression. Pre-treatment of cells with the caspase-3 specific inhibitor (z-DEVD-fmk) effectively prevented the G-Rh2-induced proteolytic activation of PKCdelta. Moreover, rottlerin, a specific PKCdelta inhibitor blocked G-Rh2-induced proapoptotic effects on the cells including the release of cytochrome c, activation of caspase-3 activity, and proteolytic cleavage and activation of PKCdelta. These results suggest that G-Rh2-induced apoptosis is functionally linked to mitochondrial dysfunction and caspase-3 activity is regulated by positive feedback with PKCdelta via the mitochondrial pathway.

Acetophenones↗