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PubMed1994

Platelet mitochondrial function in Leber's hereditary optic neuropathy.

We report the effect of the 11,778 and 3460 base pair mitochondrial DNA mutations, found in Leber's hereditary optic neuropathy (LHON), on platelet mitochondrial respiratory chain enzyme activity. We measured respiratory chain enzyme activities in platelets from 4 patients with the 3460 mutation, 17 patients with the 11,778 mutation and compared them with those of 41 healthy age-matched controls. We observed a 67% (P < 0.001) reduction in the mean NADH CoQ1 reductase (complex I) activity of the 3460 group compared to the control group. It has been shown previously that platelet mitochondrial biochemistry is affected by cigarette smoking. A significant reduction (25%, P < 0.03) in the mean complex I activity of the 11,778 group was only observed when the non-smokers within that group were compared to the non-smoking controls. The effect of smoking observed in this study may explain why previous workers have not observed a decrease in complex I activity associated with the 11,778 mutation. There was no significant change in the activity of complexes II/III or IV with either of these mutations. There was a significant increase (26%, P < 0.008) in citrate synthase (CS) activity with the non-smoking 11,778 group compared to the non-smoking control group, rising to 40% (P < 0.002) in those with this mutation who smoked. This reflects an increase in mitochondrial mass with the 11,778 mutation. This effect was not observed with the 3460 mutation even though the complex deficiency was much more severe.

Blood Platelets↗

PubMed2004

HIV neuromuscular disease and mitochondrial function.

The pathogenesis of neuromuscular syndromes in HIV-infected patients is multifactorial. Of recent concern is the mitochondrial-mediated neuromuscular pathology in HIV and its treatment. We present currently available evidence supporting the role of mitochondrial pathology in the peripheral nerve and muscle disorders due to HIV infection and antiretroviral (ARV) therapy. Three neuromuscular syndromes are discussed: distal symmetric polyneuropathy (DSP), myopathy, and HIV-associated neuromuscular weakness syndrome (HANWS). Myopathy has the most in-vivo data relating to HIV-related mitochondrial pathology, while DSP and HANWS have growing evidence of mitochondrial pathology, particularly in the context of ARV use. It is likely that these neuromuscular disorders result from a combination of mitochondrial and immunological mechanisms due to HIV and ARV therapy.

Journal Article↗

PubMed1982

Cytokinin modification of mitochondrial function.

6-Benzylaminopurine, 6-(Delta(2)-isopentenylamino)purine, 6-furfurylaminopurine, rotenone, and antimycin A inhibited oxidation of NADH by mitochondrial sonicates or submitochondrial particles (but not by intact mitochondria) from pea (Pisum sativum L., cult. Alaska) stems and mung bean (Vigna radiata L. Wilczak) hypocotyls. The above purine cytokinins can interfere with electron transport from NADH to the cytochrome system in the inner mitochondrial membrane. Adenine did not inhibit oxidation by sonicated mitochondria, and zeatin was almost ineffective. Zeatin scarcely inhibited state 3 malate respiration by intact mitochondria, but the O-formyl and O-n-propionyl esters of zeatin and the O-acetyl ester of 2-chlorozeatin were more active. Perhaps zeatin is ineffective because it does not get into the inner membranes of the isolated mitochondria, whereas the esters and other cytokinins mentioned above do. N-4-(2-chloropyridyl)-N'-Phenylurea, which has cytokinin-like effects on plant growth and development, inhibited NADH oxidation by sonicated mitochondria. It also inhibited malate, succinate, and NADH oxidation by intact mitochondria; in contrast, the latter two oxidations were not decreased by purine cytokinins.The benzyl, isopentenyl, and furfuryl aminopurines inhibited malate (but not succinate) oxidation by rat liver mitochondria, if ADP was present. In the absence of ADP, these cytokinins promoted succinate (but not malate) oxidation. Zeatin and adenine had slight, if any, effect in either situation.

Journal Article↗

PubMed1994

Changes in mitochondrial function induced in isolated guinea-pig ventricular myocytes by calcium overload.

1. Changes in [Ca2+]i and pHi, mitochondrial membrane potential (psi m) and mitochondrial [NADH] have been measured independently using fluorescent techniques in single isolated guinea-pig ventricular myocytes subjected to Ca2+ overload. 2. The changes in NADH autofluorescence on the inhibition or uncoupling of respiration are consistent with the signal emanating from the mitochondrial NADH. 3. Removal of Ca2+ and Mg2+ from the bathing Tyrode solution induced a modest fall in both [Ca2+]i and pHi, a small slowly developing depolarization of psi m and an initial fall followed by a rise in mitochondrial [NADH]. 4. In myocytes that maintained an intact sarcolemma, return to Ca(2+)-containing fluid elicited a strong but brief intracellular acidification, a rise in [Ca2+]i which generally recovered more slowly to stabilize above the initial level in Tyrode solution, a steep fall in mitochondrial [NADH] and a brief transient recovery followed by a large sustained depolarization of psi m. NADH autofluorescence and mitochondrial depolarization often reached values that were not further increased by uncoupling respiration although recovery of NADH was elicited by inhibitors of respiration. 5. These changes were reduced when the Ca2+ overload was less severe as evidenced by a reduced hypercontracture upon Ca2+ repletion. A similar reduction could be routinely achieved by elevation of [Mg2+]o during the period of Ca2+ depletion. 6. These results suggest that the well-established depletion of energy-rich phosphates that occurs on Ca2+ overload is due to the combined effects of the failure of the citric acid cycle to provide sufficient mitochondrial NADH for the respiratory chain and an uncoupling of respiration from ATP production due to depolarization of psi m. The former effect could result from the depletion of sarcoplasmic amino acids and the latter from increased Ca2+ cycling across the mitochondrial wall provoked by the elevated [Na+]i and [Ca2+]i.

Animals↗

PubMed1998

Changes in mitochondrial function resulting from synaptic activity in the rat hippocampal slice.

Digital imaging microfluorimetry was used to visualize changes in mitochondrial potential and intracellular Ca2+ concentration, [Ca2+]i, in thick slices of rat hippocampus. Electrical activity, especially stimulus train-induced bursting (STIB) activity, produced slow, prolonged changes in mitochondrial potential within hippocampal slices as revealed by fluorescence measurements with rhodamine dyes. Changes in mitochondrial potential showed both temporal and spatial correlations with the intensity of the electrical activity. Patterned changes in mitochondrial potential were observed to last from tens of seconds to minutes as the consequence of epileptiform discharges. STIB-associated elevations in [Ca2+]i were also prolonged and exhibited a spatial pattern similar to that of the mitochondrial depolarization. The mitochondrial depolarization was sensitive to TTX and glutamate receptor blockers ([Mg2+]o and CNQX or DNQX plus D-AP-5) and to the inhibition of glutamate release by activation of presynaptic NPY receptors. The monitoring of mitochondrial potential in slice preparations provides a new tool for mapping synaptic activity in the brain and for determining the roles of mitochondria in regulation of brain synaptic activity.

Animals↗

PubMed2004

Mitochondrial functional interactions between frataxin and Isu1p, the iron-sulfur cluster scaffold protein, in Saccharomyces cerevisiae.

Friedreich's ataxia is caused by a deficit in the mitochondrial protein frataxin. The present work demonstrates that in vivo yeast frataxin Yfh1p and Isu1p, the mitochondrial scaffold protein for the Fe-S cluster assembly, have tightly linked biological functions, acting in concert to promote the Fe-S cluster assembly. A synthetic lethal screen on high iron media with the mild G107D yfh1 mutant has specifically identified Isu1p. Analysis of the cellular phenotypes resulting from pairwise combinations of yfh1 and isu1 mutations, and cross-linking experiments in isolated mitochondria provide evidence for a direct interaction between Yfh1p and Isu1p.

Ferredoxins↗

PubMed1989

Effects of in vivo and in vitro exposure to rhodamine dyes on mitochondrial function of mouse embryos.

Cationic rhodamines (Rh 123 and Rh 6G) can cause developmental toxicity in mice and inhibit embryonic mitochondrial respiration following in vivo or in vitro dye exposure. Rh B, a neutral rhodamine, fails to show such effects at comparable doses. To assess effects of rhodamines on development, F0F1ATPase activity and ADP translocation were measured on gestation day (GD) 12 in embryonic and adult mitochondria. ATP synthesis in embryonic mitochondria transplacentally exposed to Rh 123 (15 mg/kg/day) or Rh 6G (0.5 mg/kg/day) given to dams by i.p. injection from GD 7 to 10 were inhibited 39% and 49%, respectively. When isolated mitochondria were treated, dose-dependent inhibition was seen; at 5 micrograms of dye/mg mitochondrial protein, ATP synthesis was inhibited 65% and 81% by Rh 123 and Rh 6G, respectively. When F0F1ATPase activity was assessed, in vitro Rh 123 and Rh 6G exposures at levels up to 8 micrograms/mg mitochondrial protein resulted in enzyme inhibition, but at 10 micrograms/mg, ATPase activity was stimulated. Uncoupler-stimulated ATPase activity was also inhibited. ADP translocation was decreased by 19.1% and 37.7% by Rh 123 and Rh 6G, respectively, at dye concentrations of 20 micrograms/mg. Results of in vitro exposure of maternal liver mitochondria were similar to those for embryonic mitochondria, whereas liver from dams exposed in vivo on GD 7-10 was unaffected on GD 12. In vivo or in vitro treatment with Rh B did not affect any embryonic or maternal parameters. Such results support the hypothesis that inhibition of mitochondrial energy metabolism is a mechanism for the developmental toxicity of cationic rhodamines.

Adenosine Triphosphate↗

PubMed2004

Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain.

Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (DeltaPsim), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex I, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain DeltaPsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis.

Adenosine Triphosphate↗

PubMed2001

Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function.

Mitochondria play a central role in energy metabolism, Ca(2+) signalling, aging and cell death. To control cytosolic or mitochondrial Ca(2+) concentration, mitochondria possess several Ca(2+)-transport systems across the inner membrane. However, the pathway for Ca(2+) crossing the outer membrane has not been directly addressed. We report that purified voltage-dependent anion channel (VDAC) reconstituted into lipid bilayers or liposomes is highly permeable to Ca(2+). VDAC contains Ca(2+)-binding sites that bind Ruthenium Red (RuR), La(3+) and that RuR completely closed VDACs in single or multichannel experiments. Energized, freshly prepared mitochondria accumulate Ca(2+) (500-700 nmol/mg of protein), and subsequently released it. The release of Ca(2+) is accompanied by cyclosporin A-inhibited swelling, suggesting activation of permeability transition pore (PTP). RuR and ruthenium amine binuclear complex, when added to mitochondria after Ca(2+) accumulation has reached a maximal level and before PTP is activated, prevented the release of Ca(2+) and the accompanied mitochondrial swelling. RuR also prevented PTP opening promoted by atractyloside, an adenine nucleotide translocase inhibitor. These results suggest that VDAC, located in the mitochondrial outer membrane, controls Ca(2+) transport into and from the mitochondria, and that the inhibition of Ca(2+) uptake by RuR and La(3+) may result from their interaction with VDAC Ca(2+)-binding sites. Inhibition of PTP opening or assembly by RuR and ruthenium amine binuclear complex suggest the involvement of VDAC in PTP activity and/or regulation. The permeability of VDAC to Ca(2+) and its binding of Ca(2+), suggest that VDAC has a role in regulation of the mitochondrial Ca(2+) homoeostasis.

Animals↗

PubMed2005

Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine.

The understanding of the involvement of mitochondrial oxidative phosphorylation (OXPHOS) in the aging process has often been biased by the different methodological approaches as well as the choice of the biological material utilized by the various groups. In the present paper, we have carried out a detailed analysis of several bioenergetic parameters and oxidative markers in brain and heart mitochondria from young (2 months) and old (28 months) rats. This analysis has revealed an age-related decrease in respiratory fluxes in brain but not in heart mitochondria. The age-related decrease in respiratory rate (-43%) by NAD-dependent substrates was associated with a consistent decline (-40%) of complex I activity in brain mitochondria. On the other hand, heart mitochondria showed an age-related decline of complex II activity. Both tissues showed, however, an age-associated accumulation of oxidative damage. We have then performed the same analysis on old (28 months) rats subjected to a long-term (16 months) diet containing the antioxidant N-acetylcysteine (NAC). The treated old rats showed a slight brain-specific improvement of mitochondrial energy production efficiency, mostly with NAD-dependent substrates, together with a decrease in carbonyl protein content and an increase in the amount of protein thiols of brain cytosolic fraction. A full recovery of complex II activity was detected in heart mitochondria from NAC-treated old rats. The present work documents the marked tissue specificity of the decline of bioenergetic functions in isolated mitochondria from aged rats and provides the first data on the effects of a long-term treatment with N-acetylcysteine.

Acetylcysteine↗

PubMed2005

Beta-carotene breakdown products may impair mitochondrial functions--potential side effects of high-dose beta-carotene supplementation.

Beta-carotene (BC) and other carotenoids are mainly considered as belonging to the group of micronutrients. As they are contained in fruit and vegetables and thus part of human diet, a regular low-dose intake from natural sources is normally assured. In the last decade high-dose supplementation with synthetic carotenoids has been used successfully in the treatment of diseases believed to be associated with oxidative stress. However, in a few clinical studies harmful effects have been observed as well, e.g., a higher incidence of lung cancer after BC was given in high doses to smokers. Our studies aim at shedding light on the causal mechanisms of the known side effects that we have investigated. Possibilities of preventing them are discussed. Obviously, on certain conditions of high-dose carotenoid supplementation, both the antioxidant and prooxidant reactions may arise. Carotenoid breakdown products (CBP) including very reactive aldehydes and epoxides are formed during oxidative attack in the course of antioxidative action. Carotenoid breakdown products inhibit state 3 respiration of isolated rat liver mitochondria at concentrations between 0.5 and 20 microM. In vivo stimulated neutrophils might represent an important source for the generation of CBP, and the lung might be a critical organ in CBP formation. The inhibition of mitochondrial state 3 respiration by CBP is accompanied by a reduced content of protein sulfhydryl groups, decreasing glutathione levels and redox state, and also elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favour functional deterioration of the adenine nucleotide translocator (ANT). The findings reflect a basic mechanism of the side effects of BC supplementation in circumstances of severe oxidative stress induced by CBP representing a class of lipid oxidation products. We are striving for safe conditions of carotenoid supplementation in order to protect patients in need of this kind of medical treatment from possible side effects, such as unwanted prooxidative reactions.

Animals↗

PubMed2005

Drugs targeting mitochondrial functions to control tumor cell growth.

Mitochondria, the power houses of the cell, are at the cross-road of many cellular pathways. They play a central role in energy metabolism, regulate calcium flux and are implicated in apoptosis. Mitochondrial dysfunctions have been associated with various physiopathological disorders, especially neurodegenerative diseases and cancer. Structurally diverse pharmacological agents have shown direct effects on mitochondria ultra-structures and functions, either at the DNA level or upon targeting proteins located in the inner or outer mitochondrial membranes. The brief review deals with the molecular targets and mechanisms of action of chemically diverse small molecules acting on specific mitochondrial loci, such as the respiratory chain, DNA biogenesis, potassium channels, the Bcl-2 protein and the permeability transition pores (PTP). Drugs, which specifically compromise the structural and functional integrity of mitochondria, may provide novel opportunities to combat cancer cell proliferation, providing that these molecules can be selectively delivered to tumor sites. Different examples reported here show that mitochondrial insult or failure can rapidly lead to inhibition of cell survival and proliferation. Mitochondrial impairment may be a successful anti-cancer strategy.

Animals↗

PubMed1980

Genetic interactions in the control of mitochondrial functions in Paramecium. I. Interactions between nuclear genes.

The genetic and physiological properties of two nuclear mutants of Paramecium tetraurelia affecting mitochondrial properties, and first screened as resistant to tetrazolium (TTC) are described. The mutant TTC64-1R is strongly deficient in cytochrome c and the mutant TTC66pR is partially deficient in cytochrome aa3; both mutants display cyanide insensitive respiration in exponential growth phase. In the double mutant TTC64-1R -- TTC66pR/TTC64-1R -- TTC66pR the deficiency in cytochrome aa3 due to the TTC66pR mutation is suppressed. The mutation TTC64-1R does not suppress cytochrome aa3 deficiencies due to mitochondrial mutations, but does interact with another nuclear mutation, cl1, (compatible only with mitochondria deficient in cytochrome oxidase) in such a way that the double mutant TTC64-1R -- cl1/TTC64-1R -- cl1 displays a normal amount of cytochrome aa3. The possible mechanisms and physiological significance of these suppressive effects are discussed.

Animals↗

PubMed2002

Nutrient-gene interactions in mitochondrial function: vitamin A needs are increased in BHE/Cdb rats.

The BHE/Cdb rat has a maternally inherited mutation in the ATPase 6 mitochondrial gene that associates with impaired oxidative phosphorylation (OXPHOS) and glucose intolerance. A longevity study revealed that feeding an egg-rich (vitamin A-rich) diet delayed the onset of impaired glucose tolerance. Two experiments were conducted to test the hypothesis that BHE/Cdb rats require more dietary vitamin A than normal rats. Experiment 1 was a dose-response study examining OXPHOS in BHE/Cdb rats fed one of six levels of vitamin A. In experiment 2 BHE/Cdb and Sprague-Dawley rats were used. The rats were depleted of retinol stores, then repleted with 4 or 12 IU vitamin A/g diet. Vitamin A status was assessed in depleted, never depleted, and depleted/repleted rats. OXPHOS was optimized at 4 IU/g diet for the Sprague-Dawley rats and 12 IU/g diet for the BHE/Cdb rats. These results suggested that the criteria for vitamin intake adequacy in the BHE/Cdb rats is the optimization of mitochondrial OXPHOS. Using this criteria, we conclude that diabetes-prone BHE/Cdb rats require more dietary vitamin A than normal rats.

Adenosine Triphosphatases↗

PubMed2003

Investigation of mitochondrial function in hereditary spastic paraparesis.

Following the association of hereditary spastic paraparesis (HSP) with mutation in the paraplegin gene (SPG7) and mitochondrial dysfunction, we wished to investigate whether mitochondrial dysfunction might be associated with other forms of HSP. Five cases of HSP caused by mutation in the spastin gene (SPG4) and nine cases with HSP with mutation in the spastin and paraplegin genes excluded (non-SPG4/SPG7), were investigated for mitochondrial dysfunction. Muscle tissue from the HSP groups and a control group was analysed histochemically and spectrophotometrically for mitochondrial dysfunction. A significant decrease in mitochondrial respiratory chain complexes I and IV was demonstrated in the non-SPG4/SPG7 group. No abnormality was detected in the SPG4 group. We therefore conclude that there is evidence for mitochondrial dysfunction in non-SPG4/SPG7 HSP. There is no evidence for mitochondrial dysfunction in the pathogenesis of spastin-related HSP.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1998

Mitochondrial function as a determinant of recovery or death in cell response to injury.

Many pathological conditions can be the cause or the consequence of mitochondrial dysfunction. For instance anoxia, which is initiated by a critical reduction of oxygen availability for mitochondrial oxidations, is followed by a wide variety of mitochondrial alterations. A crucial role in the evolution of cell injury is to be attributed to the direction of operation of the F0F1 ATPase, which may turn mitochondria into the major consumers of cellular ATP in the futile attempt to restore the proton electrochemical gradient. On the other hand, functional mitochondria can paradoxically accelerate or exacerbate cell damage. This concept is particularly relevant for the ischemic myocardium. Indeed, inhibition of the respiratory chain or addition of uncouplers of oxidative phosphorylation can both limit the extent of enzyme release in the intact heart and prevent the onset of irreversible morphological changes in isolated myocytes. From studies on different tissues in a variety of pathological conditions a general consensus emerges on the role of intracellular Ca2+ overload as a pivotal link between cellular alterations and mitochondrial dysfunction. Oxidative phosphorylation is reduced by a massive mitochondrial uptake of Ca2+, resulting in a vicious cycle whereby the reduced ATP availability is followed by a failure of the mechanisms which extrude Ca2+ from the sarcoplasm. In addition, the rise in [Ca2+]i could promote opening of the cyclosporin-sensitive mitochondrial permeability transition pore, leading to a sudden deltapsi(m) dissipation. Here, we review the changes in intracellular and intramitochondrial ionic homeostasis occurring during ischemia and reperfusion. In particular, we evaluate the potential contribution of the permeability transition pore to cellular damage and discuss the mechanisms which can determine the cellular fate from a mitochondrial point of view.

Adenine Nucleotides↗

PubMed2003

Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy.

BACKGROUND: Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. We previously reported that 5-HT2B receptor ablation in mice leads to dilated cardiomyopathy. In this study, we investigated the pathological consequence of overexpressing 5-HT2B receptors in heart in vivo. METHODS AND RESULTS: We have generated transgenic mice overexpressing the Gq-coupled 5-HT2B receptor specifically in heart. We found that overexpression of 5-HT2B receptor in heart leads to ventricular hypertrophy as the result of increased cell number and size. Increased atrial natriuretic peptide and myosin heavy chain expression demonstrated activation of the molecular program for cardiac hypertrophy. Echocardiographic analysis indicated the presence of thickened ventricular free wall without alteration of the systolic function, showing that transgenic mice have compensated hypertrophy. Electron microscopic analysis revealed structural abnormalities including mitochondrial proliferation, as also manifested by histological staining. Transgenic mouse heart displayed a specific reduction in the expression levels of the adenine nucleotide translocator associated to increase in the succinate dehydrogenase and cytochrome C oxidase mitochondrial activities. CONCLUSIONS: Our results constitute the first genetic evidence that overexpression of the 5-HT2B receptor in the heart leads to compensated hypertrophic cardiomyopathy associated with proliferation of the mitochondria. This observation suggests a role for mitochondria in the hypertrophic signaling that is regulated by serotonin. These transgenic mice provide a new genetic model for hypertrophic heart disease.

Animals↗

PubMed1998

Mitochondrial function in Babesia microti and Babesia rodhaini.

The role of mitochondria in the energy metabolism of Babesia microti and Babesia rodhaini was investigated. A variety of mitochondrial inhibitors showed greater sensitivity to B. microti than to B. rodhaini. Additionally, alpha-glycerophosphate- and succinate-cytochrome c reductase activities in the crude mitochondrial fraction from B. microti were substantially higher than those from B. rodhaini. Our results suggest that the mitochondria of these parasites possess a series of "classical" apparati for energy production and their relative functional role may be quantitatively greater in B. microti when compared with B. rodhaini.

ATP Synthetase Complexes↗