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PubMed2006

Immunohistochemical and ultrastructural abnormalities in muscle from a patient with sensorineural hearing loss related to a 1555 A-to-G mitochondrial mutation.

Genetic studies indicate that hereditary susceptibility of the inner ear to aminoglycoside antibiotic toxicity is caused by a nucleotide 1555 A-to-G mutation in the mitochondrial 12S rRNA gene. Although the phenotype associated with this mutation is nonsyndromic hearing loss, the possibility remains that there could be effects on other tissues that, like the inner ear, contain numerous mitochondria, particularly muscle. We obtained a temporalis muscle specimen from a deaf patient with the A1555G mutation and found informative pathologic features, including mosaic activity of cytochrome c oxidase immunoreactivity and mitochondrial ultrastructure. These findings suggest that mitochondrial dysfunction from the A1555G mutation extends beyond the inner ear.

Electron Transport Complex IV↗

PubMed2005

Glycyrrhizae Radix attenuates peroxynitrite-induced renal oxidative damage through inhibition of protein nitration.

We investigated the protective effects of Glycyrrhizae Radix extract against peroxynitrite (ONOO-)-induced oxidative stress under in vivo as well as in vitro conditions. The extract showed strong ONOO- and nitric oxide (NO) scavenging effects under in vitro system, in particular higher activity against ONOO-. Furthermore, elevations of plasma 3-nitrotyrosine levels, indicative of in vivo ONOO- generation and NO production, were shown using a rat in vivo ONOO(-)-generation model of lipopolysaccharide injection plus ischemia-reperfusion. The administration of Glycyrrhizae Radix extract at doses of 30 and 60 mg/kg body weight/day for 30 days significantly reduced the concentrations of 3-nitrotyrosine and NO and decreased inducible NO synthase activity. In addition, the nitrated tyrosine protein level and myeloperoxidase activity in the kidney were significantly lower in rats given Glycyrrhizae Radix extract than in control rats. However, the administration of Glycyrrhizae Radix extract did not result in either significant elevation of glutathione levels or reduction of lipid peroxidation in renal mitochondria. Moreover, the in vivo ONOO- generation system resulted in renal functional impairment, reflected by increased plasma levels of urea nitrogen and creatinine, whereas the administration of Glycyrrhizae Radix extract reduced these levels significantly, implying that the renal dysfunction induced by ONOO- was ameliorated. The present study suggests that Glycyrrhizae Radix extract could protect the kidneys against ONOO- through scavenging ONOO- and/or its precursor NO, inhibiting protein nitration and improving renal dysfunction caused by ONOO-.

Animals↗

PubMed1979

Temporal relation between onset of cell anoxia and ischemic contractile failure. Myocardial ischemia and left ventricular failure in the isolated, perfused rabbit heart.

Contractile dysfunction is characteristic of the acutely ischemic myocardium. This study was undertaken to assess the temporal relations between the onset of cell anoxia and ischemic contractile failure in isolated, isovolumetric contracting rabbit hearts. High speed epicardial fluorescence photography using reduced nicotinamide adenosine nucleotide (NADH) was used to identify areas of cell anoxia. The onset of ischemia was correlated with deterioration of pressure generation over the course of sequential 60 second coronary arterial occlusions. In the isovolumetric contracting rabbit heart, areas of ischemia were detected 2 seconds after coronary occlusion. Significant reduction in peak systolic pressure occurred at 6 seconds of ischemic time and pressure continued to decrease throughout the 60 second period of coronary occlusion. NADH accumulation indicates imbalance of myocardial oxygen supply and demand and the cessation of oxygen utilization by the mitochondria. The results of this study indicate that ischemia is detectable within 1 to 2 seconds after coronary occlusion and that ischemic ventricular dysfunction occurs several seconds thereafter. Myocardial oxygen reserve is negligible.

Animals↗

PubMed2005

Explaining the phenomenon of nitrate tolerance.

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase have been proposed as superoxide sources. Superoxide and vascular NO rapidly form peroxynitrite, which aggravates tolerance by promoting NO synthase uncoupling and inhibition of soluble guanylyl cyclase and prostacyclin synthase. This oxidative stress concept may explain why radical scavengers and substances, which reduce oxidative stress indirectly, are able to relieve tolerance and endothelial dysfunction. Recent work has defined a new tolerance mechanism, ie, an inhibition of mitochondrial aldehyde dehydrogenase, the enzyme that accomplishes bioactivation of nitroglycerin, and has identified mitochondria as an additional source of reactive oxygen species. Nitroglycerin-induced reactive oxygen species inhibit the bioactivation of nitroglycerin by thiol oxidation of aldehyde dehydrogenase. Both mechanisms, increased oxidative stress and impaired bioactivation of nitroglycerin, can be joined to provide a new concept for nitroglycerin tolerance and cross-tolerance. The consequences of these processes for the nitroglycerin downstream targets soluble guanylyl cyclase, cGMP-dependent protein kinase, cGMP-degrading phosphodiesterases, and toxic side effects contributing to endothelial dysfunction, such as inhibition of prostacyclin synthase, are discussed in this review.

Aldehyde Dehydrogenase↗

PubMed2006

Detrimental deletions: mitochondria, aging and Parkinson's disease.

As individuals enter their 80s, they are inevitably confronted with the problem of neuronal loss in the brain. The incidence of the common movement disorder 'mild parkinsonian signs' (MPS) is approximately 50% over the age of 85 years. It has long been known that the loss of dopaminergic neurons in the substantia nigra pars compacta is a neuropathological hallmark of Parkinson's disease (PD). Recently, two papers present clear evidence for a high burden of mitochondrial DNA deletions within substantia nigra neurons in aged individuals and individuals with PD, pointing towards a common pathway inevitably leading to neuronal dysfunction and death.

Aged↗

PubMed1981

Mitochondrial alterations in the spinal ganglion neurons in ageing rats.

An ultrastructural study of the mitochondria was performed in the 3-, 24-, and 32-month-old rats. Accumulation of "unusual" substances or structures was the most striking characteristic in senescent neuron mitochondria. Tubular or filamentous inclusions, modifications in matrix density, deposit of glycogen particles and electron-dense globules were observed. The various nature of these alterations and their different situation in the cristae or in the matrix, suggested that they could be the result of some specific oxidative metabolism dysfunctions associated with ageing.

Aging↗

PubMed2005

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast.

Autophagy, a highly regulated programme found in almost all eukaryotes, is mainly viewed as a catabolic process that degrades nonessential cellular components into molecular building blocks, subsequently available for biosynthesis at a lesser expense than de novo synthesis. Autophagy is largely known to be regulated by nutritional conditions. Here we show that, in yeast cells grown under nonstarving conditions, autophagy can be induced by mitochondrial dysfunction. Electron micrographs and biochemical studies show that an autophagic activity can result from impairing the mitochondrial electrochemical transmembrane potential. Furthermore, mitochondrial damage-induced autophagy results in the preferential degradation of impaired mitochondria (mitophagy), before leading to cell death. Mitophagy appears to rely on classical macroautophagy machinery while being independent of cellular ATP collapse. These results suggest that in this case, autophagy can be envisioned either as a process of mitochondrial quality control, or as an ultimate cellular response triggered when cells are overwhelmed with damaged mitochondria.

Adenosine Triphosphate↗

PubMed1993

Effects of psychosine (galactosylsphingosine) on the survival and the fine structure of cultured Schwann cells.

The cytotoxicity of psychosine (galactosylsphingosine) for cultured rat Schwann cells was studied by maintaining them in medium containing 1, 10, 50, 75 and 100 microM psychosine for 24, 48 and 72 hours (h). When incubated in 50-100 microM concentrations of psychosine for 24 h, 52-99% of cultured Schwann cells did not survive. Lower concentrations (1-10 microM) did not significantly reduce Schwann cell numbers for the first 24 h. However, only 43-69% of cultured Schwann cells survived in these low concentrations for 48 h, and substantially fewer remained after 72 h of incubation. During incubations in psychosine, bipolar processes of Schwann cells retracted; the resulting oval and rounded Schwann cells still were S-100 positive. When these Schwann cells were transferred into normal medium, their processes elongated quickly. When examined with the electron microscope, the cytoplasm of Schwann cells incubated in psychosine contained numerous membranous inclusions and fewer mitochondria, some of which were swollen. There also were fewer profiles of granular endoplasmic reticulum and some had widely dilated cisternae. These results suggest that 1) exogenous psychosine in concentrations of 1 microM and greater is cytotoxic for cultured rat Schwann cells; 2) psychosine has reversible toxic effects and its turnover is rapid; and 3) psychosine produces membranous inclusions and abnormalities in the mitochondria and granular endoplasmic reticulum of cultured Schwann cells. Our findings support the hypothesis that the accumulation of psychosine in human and murine globoid cell leukodystrophy is toxic for Schwann cells, produces changes in their capacity to maintain myelin, and leads to Schwann cell dysfunction.

Animals↗

PubMedDate not supplied

Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress.

BACKGROUND AND AIM: This study was undertaken to test the hypothesis that hyperglycaemia induces the generation of reactive oxygen species (ROS) by mitochondria and that the oxidative stress thereby exerted is diminished by treatment with metformin. As a parameter of mitochondrial ROS formation, the activity of mitochondrial aconitase activity was determined using Goto-Kakizaki (GK) rats as model of type 2 diabetes. METHODS: In parallel with the development of diabetes (glucose, insulin), the generation of oxidative stress was determined in aortic tissue, heart and kidney of GK rats by measurement of lipid peroxides, oxidized proteins (carbonyl activity) and mitochondrial aconitase activity. Vascular activity was determined in aortae by measuring the endothelium-dependent vasodilatation in response to acetylcholine, and vasoconstriction in response to phenylephrine. RESULTS: At the age of 12-14 weeks, blood glucose levels rose dramatically from 7.5 up to 16.2 mM, indicating the manifestation of an overt diabetes. In addition, the glucose tolerance was impaired. The increase in blood glucose was not accompanied by changes in plasma insulin. Whereas the lipid peroxides in plasma only showed a tendency to increase, the amount of oxidized proteins (carbonyl moieties) increased from 4.6 to 10.9 micromol/mg protein (2.4 fold). In addition, the lipid peroxides in tissue were increased. Mitochondrial aconitase activity was reduced in the aorta and kidney, but not in the heart of diabetic animals. Treatment with metformin nearly normalized the hyperglycaemia and prevented the rise in carbonyl, tissue lipid peroxides and the fall in aconitase activity. Whereas the endothelium-dependent vasodilatation was not affected by the diabetes, the reaction of aortae in response to phenylephrine was strongly enhanced, changes which were prevented by treatment with metformin. CONCLUSIONS: These observations provide in vivo evidence that the generation of ROS plays an important role in the onset of diabetes and the development of vascular dysfunction in GK rats with type 2 diabetes.

Animals↗

PubMed2004

Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia.

In this study, heart and diaphragm mitochondria produced 0.69 and 0.77 nmol nitric oxide (NO)/min mg protein, rates that account for 67 and 24% of maximal cellular NO production, respectively. Endotoxemia and septic shock occur with an exacerbated inflammatory response that damages tissue mitochondria. Skeletal muscle seems to be one of the main target organs in septic shock, showing an increased NO production and early oxidative stress. The kinetic properties of mitochondrial nitric oxide synthase (mtNOS) of heart and diaphragm were determined. For diaphragm, the KM values for O2 and L-Arg were 4.6 and 37 microM and for heart were 3.3 and 36 microM. The optimal pH for mtNOS activity was 6.5 for diaphragm and 7.0 for heart. A marked increase in mtNOS activity was observed in endotoxemic rats, 90% in diaphragm and 30% in heart. Diaphragm and heart mitochondrial O2*- and H2O2 production were 2- to 3-fold increased during endotoxemia and Mn-SOD activity showed a 2-fold increase in treated animals, whereas catalase activity was unchanged. One of the current hypotheses for the molecular mechanisms underlying the complex condition of septic shock is that the enhanced NO production by mtNOS leads to excessive peroxynitrite production and protein nitration in the mitochondrial matrix, causing mitochondrial dysfunction and contractile failure.

Animals↗

PubMed1995

Molecular changes of titin in left ventricular dysfunction as a result of chronic hibernation.

Cardiomyocytes of chronic hibernating myocardium are affected by partial to complete loss of sarcomeres, accumulation of glycogen, adaptations in size and shape of mitochondria, reorganisation of nuclear chromatin and depletion of sarcoplasmic reticulum. The nature of these changes, which from a purely morphologic viewpoint are akin to dedifferentiation, needed further clarification at the molecular level. For this purpose we have studied the expression and reorganization of titin, one of the earliest markers of cardiomyocytes differentiation. By use of monoclonal antibodies, recognizing different epitopes distributed over the whole length of the titin molecule, we were able to detect changes in its molecular organization as a result of chronic hibernation. The epitopes of the titin molecule attached to the Z-disc and those present close to the M-line remained detectable at all stages of hibernation, while epitopes at the A-I junction and parts of the myosin anchoring region of the molecule became masked or were lost. A fragmented or punctuated appearance of the titin staining pattern with antibodies to A-I junction related epitopes is found in cells which we consider to represent a more advanced stage of dedifferentiation. Changes in the distribution of the titin molecule or its molecular environment in hibernating myocardium resemble at least in part changes occurring during muscle cell differentiation, although in reversed order.

Animals↗

PubMed1996

Normal mitochondrial DNA and respiratory chain activity in familial dysautonomia fibroblasts.

Familial dysautonomia (FD), an autosomal recessive disease mapped to chromosome 9q31, is a sensory and autonomic neuropathy of unknown etiology. We have previously reported light microscopic pleiomorphic changes in cells suggestive of altered plasma membranes, an increase in globotriaosylceramide (Gb3), reflected by an increase in Gb3 on the surface of the plasma membrane, and a decrease in the rate and amount of ganglioside synthesized. In unrelated studies, we demonstrated that storage of glycospingolipids (GSL) is deleterious to mitochondrial function. Recently, mitochondrial dysfunction has been associated with neurodegenerative disease, superimposed on an autosomal inheritance pattern. We have now probed Southern blots of total FD fibroblast DNA, digested with BamHI, EcoRII, and/or PvuII, with purified placental 32P-labeled mitochondrial DNA. The sizes of all FD mitochondrial DNAs were normal (16,569 bp), some containing previously identified BamHI polymorphisms. Lactate/pyruvate ratios, and activities of Complexes II and III, matched those of control cells. Electron microscopy revealed morphologically normal mitochondria, in conjunction with a normal oxidative state, determined using the redox dyes Mito Tracker CMXR and CMXR-H2 and fluorescence microscopy. We conclude that mitochondrial dysfunction, due to GSL accumulation, changes in mitochondrial DNA, or mutation of a chromosome 9q gene involved in mitochondrial function, is neither a primary nor a secondary cause of FD, as determined by a study of FD fibroblasts.

Blotting, Southern↗

PubMed2005

Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.

Mitochondria play an important role in energy production, Ca2+ homeostasis and cell death. In recent years, the role of the mitochondria in apoptotic and necrotic cell death has attracted much attention. In apoptosis and necrosis, the mitochondrial permeability transition (mPT), which leads to disruption of the mitochondrial membranes and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. We therefore created mice lacking cyclophilin D (CypD), a protein considered to be involved in the mPT, to analyse its role in cell death. CypD-deficient mice were developmentally normal and showed no apparent anomalies, but CypD-deficient mitochondria did not undergo the cyclosporin A-sensitive mPT. CypD-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload. In addition, CypD-deficient mice showed a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Our results indicate that the CypD-dependent mPT regulates some forms of necrotic death, but not apoptotic death.

Animals↗

PubMed2002

Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation.

UNLABELLED: Adult-onset type 2 citrullinaemia (CTLN2) is caused by a deficiency of the citrin protein encoded by the SLC25A13 gene. Citrin, an aspartate glutamate carrier in mitochondria, is an essential component of the malate-aspartate NADH shuttle. Recently, citrin deficiency has been reported to manifest as neonatal intrahepatic cholestasis. We report here five cases with neonatal intrahepatic cholestasis caused by citrin deficiency. Genetic diagnosis revealed compound heterozygotes of 851del4/IVS11 + 1G-->A in two patients, IVS11 + 1G-->A/E601X, and IVS11 + 1G-->A/unknown in each one patient and homozygote for S225X in one patient. All cases revealed high levels of alpha-fetoprotein, which are not observed in CTLN2 patients. The condition was self-limiting and spontaneously disappeared after 5-7 months of age in four patients. However, one patient developed hepatic dysfunction from the age of 6 months and required a living-related liver transplantation at the age of 10 months. The patient showed complete recovery after transplantation, and now at the age of 3 years, shows normal growth and mental development. CONCLUSION: we report the first case of neonatal intrahepatic cholestasis caused by citrin deficiency with severe hepatic dysfunction requiring a living-related liver transplantation. Patients with this disorder should be followed up carefully, even during infancy.

Calcium-Binding Proteins↗

PubMed1980

Mitochondrial function of rat liver in biliary obstruction.

An investigation was performed of the liver mitochondrial respiratory function in rats after 1, 3 and 6 weeks of biliary obstruction and the following results were obtained: 1) Various parameters of liver mitochondrial respiratory function, such as respiratory control ratio, ADP/O, O2 consumption in state 3 respiration and adenosine triphosphate synthesis were found to decrease with prolongation of biliary obstruction. 2) The mitochondrial respiratory enzymes, cytochrome a (+a3) and cytochrome c(+c1) showed that both decreased in contents with prolongation of obstruction, particularly the latter. 3) The activation ratio of ATPase (latent ATPase/dinitrophenol stimulated ATPase) was increased after long term biliary obstruction, which was thought to indicate the severe damage of mitochondrial membrane. 4) Investigation of the respiratory function with the various respiratory substrates showed that the locations of mitochondrial respiratory inhibition in obstructive jaundice are at sites 1 and 2, which is the same as the situation seen in nonspecific damage of mitochondria. 5) There was a high degree of mitochondrial respiratory disturbance by bile acids, particularly CDCA, which is thought to be one of the causal factors of liver dysfunction in obstructive jaundice. 6) Mitochondrial respiratory function was markedly disturbed in hypotension, and the degree of which correlated with length of time of biliary obstruction.

Adenosine Triphosphatases↗

PubMed1994

Tissue iron overload and mechanisms of iron-catalyzed oxidative injury.

Tissue iron overload causes clinical syndromes that involve the heart, liver, and pancreas. While tissue iron uptake occurs by both transferrin-dependent and independent processes, tissue uptake in the iron overload syndromes occurs predominantly via transferrin-independent mechanisms. Increased redox-active iron present in hemeproteins and the cytosolic iron pool can catalyze oxidative damage to lipids, proteins, and nucleic acids, either by oxyradical dependent or independent mechanisms. Iron-catalyzed injury results in damage to cell constituents, including mitochondria, lysosomes, and the sarcolemmal membrane. These mechanisms of iron-mediated damage are involved in the pathogenesis of organ dysfunction in primary hemochromatosis, transfusion-related iron overload, ischemia-reperfusion injury, and cardiac anthracycline toxicity.

Animals↗

PubMed1984

Mitochondrial abnormalities in cortical dendrites from patients with early forms of subacute sclerosing panencephalitis (SSPE).

Biopsy fragments from the frontal cortex of two patients with early forms of subacute sclerosing panencephalitis (SSPE) were studied with ultrastructural methods. Special attention was given to mitochondrial abnormalities observed in dendrites from the three superficial cortical layers. Some of the mitochondria presented atypical elongated cristae parallel to the longer axis of the organelle and closely opposite each other. The surface of these cristae is undulated, and the intracristal space is regularly septate. As these abnormal mitochondria appeared in dendrites, which in later stages of the disease are supposed to degenerate, it is advanced that these abnormalities could be precursors of dendritic changes and be possibly related to the precocious, insidious mental changes which characterize the early forms of the disease, as it is known that the disruption of the dendritic domain is linked with neuronal dysfunction.

Cerebral Cortex↗

PubMed2026

Norgestrel drives mitochondrial collapse and plasma membrane impairment in Pacific oyster (Crassostrea gigas) sperm by triggering premature acrosome reaction.

The toxic mechanisms of norgestrel (NGT), an emerging marine pollutant, on the sperm from externally fertilized invertebrates remain elusive. This study employed an integrated physiological and multi-omics framework to elucidate how NGT (10 and 1000 ng/L) disrupts acrosome reaction (AR) signaling machinery, thereby impairing the functional integrity of Pacific oyster (Crassostrea gigas, also known as Magallana gigas) sperm. Exposure to NGT triggered a significant, dose-dependent premature AR, characterized by elevated acrosin activity and a loss of acrosomal integrity. Multi-omics integration supports a model in which this premature exocytosis is linked to signaling disturbances, including disruption of calcium signaling and reduced transcript abundance of calmodulin (CaM) and the primary recognition protein zonadhesin (Zan). This signaling interference induced an premature AR, subsequently driving a cascade of bioenergetic and structural failures. At the mitochondrial level, NGT induced abnormal mitochondrial permeability transition pore (mPTP) opening and elevated the transcript levels of antioxidant defense genes (e.g., peroxiredoxin-5, PRDX5). These alterations indicate the occurrence of mitochondrial collapse. Concurrently, scanning electron microscopy verified localized plasma membrane wrinkling and pore formation in sperm. In addition, NGT exposure decreased the transcript abundance of cytoskeleton-related genes, including solute carrier family 26 member 6 (SLC26A6), actin (ACT), and tubulin polymerization promoting protein family member 3 (TPPP3). These molecular changes further disrupted membrane phospholipid homeostasis, as represented by altered glycerophospholipid metabolism. At the same time, cumulative cellular stress was associated with decreased transcript abundance of cytoprotective factors (e.g., baculoviral IAP repeat-containing proteins, birc2) and changes in apoptosis-related genes consistent with activation of a caspase-8-mediated apoptotic programme. In conclusion, NGT, as a representative synthetic progestin, exerts reproductive toxicity by interfering with signaling mediators to induce premature AR, which subsequently exhausts metabolic energy and triggers plasma membrane impairment. These findings provide a critical mechanistic basis for the aquatic ecological risk assessment of synthetic progestins.

Animals↗