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PubMed2000

Differences in nuclear DNA fragmentation and mitochondrial integrity of semen and prepared human spermatozoa.

Sperm DNA integrity is essential for accurate transmission of genetic material to offspring. Fragmentation of genomic DNA is an initial hallmark of apoptosis (programmed cell death). The aim of this study was to determine sperm nuclear DNA integrity and mitochondrial function, to quantify possible apoptosis and to investigate any relationship between these parameters. Semen samples (n = 25) were prepared by discontinuous Percoll density centrifugation (95.0:47.5). DNA integrity was determined using a modified alkaline single cell gel electrophoresis (Comet) assay. DNA fragmentation, possibly indicative of apoptosis, was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Mitochondrial transmembrane potential was determined using the mitochondrial probe 5,5',6,6'-tetrachloro-1,1', 3,3'-tetraethylbenzimidazolyl carbocyanine iodide (JC-1). The DNA integrity of prepared spermatozoa was significantly greater than that of semen (P < 0.005). Further, the percentage of spermatozoa with fragmented DNA and the degree of fragmentation within these cells in prepared spermatozoa is significantly less than in semen (P < 0.005). There is a significant correlation between DNA damage quantified using the Comet assay and DNA fragmentation determined using TUNEL (R = 0.562, P < 0.01). The percentage of spermatozoa with dysfunctional, possibly apoptotic, mitochondria was significantly lower in prepared spermatozoa than in neat semen samples (P < 0.001). There was a negative correlation between the percentage of spermatozoa with dysfunctional mitochondria and the percentage of progressively motile spermatozoa (R = -0.67, P < 0.01).

Adult↗

PubMed2001

Induction of apoptosis in human lymphocytes by the herbicide 2,4-dichlorophenoxyacetic acid.

Dimethylammonium salt of 2,4-dichlorophenoxyacetic acid (DMA-2,4-D) is a widely used herbicide that is considered moderately toxic. In the present study we found that DMA-2,4-D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals and Jurkat T cells. Apoptosis induced by DMA-2,4-D was dose and time dependent, independent of Fas, TNF receptor 1 or the aromatic hydrocarbon receptor, and involved disruption of the mitochondrial transmembrane potential and activation of caspase-9. ZVAD-FMK, a broad-spectrum inhibitor of caspases, blocked DMA-2,4-D-induced apoptosis completely. While an inhibitor of caspase-9, as well as caspase-9 and caspase-3 inhibitors in combination, strongly blocked DMA-2,4-D-induced apoptosis, an inhibitor of caspase-3 had a moderate inhibitory effect. Unlike Fas-mediated apoptosis, the initiator caspase, caspase-8, was not involved in DMA-2,4-D-induced apoptosis. Transfection of Jurkat cells with Bcl-2 prevented DMA-2,4-D-induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis. Our data indicate that DMA-2,4-D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria. The activation of caspases occurs downstream of mitochondrial damage, and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis.

2,4-Dichlorophenoxyacetic Acid↗

PubMedDate not supplied

Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death.

Oxidative stress is increased in the retina in diabetes; the levels of oxidatively modified DNA and nitrosylated proteins are elevated, and antioxidant defense enzymes are impaired. The levels of superoxides are elevated in the retina, and the mitochondria become dysfunctional with proapoptotic protein, Bax, translocating from the cytosol into the mitochondria, and cytochrome c leaking out from the mitochondria. This is accompanied by increased retinal capillary cell apoptosis, and the formation of acellular capillaries and pericyte ghosts, the early signs of retinopathy in animal models of diabetic retinopathy. Inhibition of superoxides inhibits glucose -induced mitochondrial dysfunction, activation of caspase-3, and cell death in retinal capillary cells. In animal models, long-term administration of lipoic acid or other antioxidants inhibits the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine and capillary cell apoptosis in the retina. Understanding the role of mitochondria in the development of retinopathy in diabetes should help identify therapies that can neutralize superoxides and inhibit their dysfunction and, ultimately, the development of retinopathy.

Animals↗

PubMed2004

Mitochondria, synaptic plasticity, and schizophrenia.

The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.

Animals↗

PubMed2001

Cell differentiation and apoptosis of monocytic and promyelocytic leukemia cells (U-937 and HL-60) by tryptanthrin, an active ingredient of Polygonum tinctorium Lour.

Tryptanthrin, a bioactive ingredient of Polygonum tinctorium Lour., is a member of the Indigo plant family and has potent cytocidal effects on various human leukemia cells in vitro. At low concentrations, tryptanthrin enhanced the expression of cell differentiation (CD) markers in human monocytic (U-937) and promyelocytic (HL-60) leukemia cells indicative of differentiation to monocytes/macrophages. Furthermore, nitroblue tetrazolium (NBT) reductive and alpha-naphthyl butyrate esterase (NBE) activities were markedly increased after treatment. Tryptanthrin was more potent than dimethyl sulfoxide (DMSO) at inducing U-937 cell differentiation into monocytes/macrophages. After treatment with higher concentrations of tryptanthrin for 24 h, cytoplasmic vacuolation and destruction of mitochondria were observed. The leukemia cells died via apoptosis 48 h after treatment. Cytoplasmic vacuolation and apoptotic changes correlated with the dysfunction of mitochondria. Electron microscopic observations revealed marked swelling and destruction of mitochondria after exposure of the leukemia cells to tryptanthrin. Exposure to tryptanthrin enhanced Fas-induced apoptosis and increased caspase-3 activity before induction of apoptosis. These results show that low concentrations of tryptanthrin can induce differentiation of leukemia cells but higher concentrations will kill leukemia cells through apoptosis, possibly through a caspase-3/Fas antigen pathway.

Antigens, CD↗

PubMed2002

Cardiovascular hemodynamics and exercise tolerance in thyroid disease.

The heart is an organ sensitive to the action of thyroid hormone, and measurable changes in cardiovascular performance are detected with small variations in thyroid hormone serum concentrations. Most patients with thyroid disease experience cardiovascular manifestations, and the most serious complications of thyroid dysfunction occur as a result of cardiac involvement. The increased metabolic state and oxygen consumption that occur in hyperthyroid patients require an increased supply of oxygen and removal of metabolic products from the periphery. This is accomplished by increasing the cardiac output to meet the needs of the periphery. Circulation time is decreased in hyperthyroid patients, and a lowered arterial resistance and increased venous resistance promote the return of blood to the heart. Thyroid hormones may significantly decrease the strength of respiratory and skeletal muscles and affect regulatory mechanisms of adaptation to incremental effort. In hyperthyroidism, cardiovascular exercise testing and analysis of respiratory gas exchange demonstrate low efficiency of cardiopulmonary function as well as impaired chronotropic, contractile, and vasodilatatory reserves, which are reversible when euthyroidism is restored. During exercise, the increment (delta) of minute ventilation (respiratory rate x tidal volume), and oxygen pulse (oxygen uptake per heart beat) are significantly lower in dysthyroidism versus euthyroidism. Especially in older patients with thyroid dysfunction, markedly reduced workload, delta ejection fraction, and delta heart rate, both at the anaerobic threshold as well as at maximal exercise, are observed. In thyrotoxicosis, mitochondria oxidative dysfunction during exercise mostly causes intracellular acidosis, whereas in hypothyroidism, inadequate cardiovascular support appears to be one of the principal factors involved. These abnormalities partly explain why subjects with dysthyroidism are intolerant to exertion. Thus, in thyroid disease, both cardiac structures and function may remain normal at rest, however impaired cardiovascular and respiratory adaptation to effort becomes unmasked during exercise.

Age Factors↗

PubMed2006

Rapid pacing of embryoid bodies impairs mitochondrial ATP synthesis by a calcium-dependent mechanism--a model of in vitro differentiated cardiomyocytes to study molecular effects of tachycardia.

Tachycardia may cause substantial molecular and ultrastructural alterations in cardiac tissue. The underlying pathophysiology has not been fully explored. The purpose of this study was (I) to validate a three-dimensional in vitro pacing model, (II) to examine the effect of rapid pacing on mitochondrial function in intact cells, and (III) to evaluate the involvement of L-type-channel-mediated calcium influx in alterations of mitochondria in cardiomyocytes during rapid pacing. In vitro differentiated cardiomyocytes from P19 cells that formed embryoid bodies were paced for 24 h with 0.6 and 2.0 Hz. Pacing at 2.0 Hz increased mRNA expression and phosphorylation of ERK1/2 and caused cellular hypertrophy, indicated by increased protein/DNA ratio, and oxidative stress measured as loss of cellular thiols. Rapid pacing additionally provoked structural alterations of mitochondria. All these changes are known to occur in vivo during atrial fibrillation. The structural alterations of mitochondria were accompanied by limitation of ATP production as evidenced by decreased endogenous respiration in combination with decreased ATP levels in intact cells. Inhibition of calcium inward current with verapamil protected against hypertrophic response and oxidative stress. Verapamil ameliorated morphological changes and dysfunction of mitochondria. In conclusion, rapid pacing-dependent changes in calcium inward current via L-type channels mediate both oxidative stress and mitochondrial dysfunction. The in vitro pacing model presented here reflects changes occurring during tachycardia and, thus, allows functional analyses of the signaling pathways involved.

Adenosine Diphosphate↗

PubMed2002

Mitochondria, nitric oxide, and cardiovascular dysfunction.

Cardiovascular diseases encompass a wide spectrum of abnormalities with diverse etiologies. The molecular mechanisms underlying these disorders include a variety of responses such as changes in nitric oxide- (NO) dependent cell signaling and increased apoptosis. An interesting aspect that has received little or no attention is the role mitochondria may play in the vascular changes that occur in both atherosclerosis and hypertension. With the changing perspective of the organelle from simply a role in metabolism to a contributor to signal transduction pathways, the role of mitochondria in cells with relatively low energy demands such as the endothelium has become important to understand. In this context, the definition of the NO-cytochrome c oxidase signaling pathway and the influence this has on cytochrome c release is particularly important in understanding apoptotic mechanisms involving the mitochondrion. This review examines the role of compromised mitochondrial function in a variety of vascular pathologies and the modulation of these effects by NO. The interaction of NO with the various mitochondrial respiratory complexes and the role NO plays in modulating mitochondrial-mediated apoptosis in these systems will be discussed.

Animals↗

PubMed2006

Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.

Huntington's disease (HD) is a fatal, dominantly inherited disorder caused by polyglutamine repeat expansion in the huntingtin (htt) gene. Here, we observe that HD mice develop hypothermia associated with impaired activation of brown adipose tissue (BAT). Although sympathetic stimulation of PPARgamma coactivator 1alpha (PGC-1alpha) was intact in BAT of HD mice, uncoupling protein 1 (UCP-1) induction was blunted. In cultured cells, expression of mutant htt suppressed UCP-1 promoter activity; this was reversed by PGC-1alpha expression. HD mice showed reduced food intake and increased energy expenditure, with dysfunctional BAT mitochondria. PGC-1alpha is a known regulator of mitochondrial function; here, we document reduced expression of PGC-1alpha target genes in HD patient and mouse striatum. Mitochondria of HD mouse brain show reduced oxygen consumption rates. Finally, HD striatal neurons expressing exogenous PGC-1alpha were resistant to 3-nitropropionic acid treatment. Altered PGC-1alpha function may thus link transcription dysregulation and mitochondrial dysfunction in HD.

Adipose Tissue, Brown↗

PubMed2006

Meeting report: ISN forefronts in nephrology on endothelial biology and renal disease: from bench to prevention.

This ISN-sponsored Forefront in Nephrology meeting, which has brought together 120 scientists from 21 countries, has been concerned with various aspects of endothelial function and dysfunction and their contribution to progression of chronic kidney disease and/or its cardiovascular complications. The following themes were discussed in great depth: (1) phenotypical changes in the vascular endothelium - permeability, senescence, and apoptosis; (2) regulation of endothelial nitric oxide (NO) synthase function - caveolar and shear stress mechanisms, epigenetic regulation, S-nitrosylation, and Rho-kinase regulation; (3) oxidative stress and hypoxia-induced changes; (4) organellar dysfunction - lysosomes, mitochondria, and endoplasmic reticulum; (5) NO-independent mechanisms of vasomotion - epoxides, heme oxygenase-1 and carbon monoxide, thromboxane, tumor necrosis factor-alpha, and uric acid; (6) endothelial crosstalk with podocytes, monocytes, smooth muscle cells, and platelets; (7) candidate clinical biomarkers of endothelial dysfunction - functional testing of macro- and micro-vascular functions, surrogate markers, circulating detached endothelial cells, and endothelial precursor cells; and culminated in Round Table discussion on the diagnosis of endothelial dysfunction and its treatment options. In conclusion, this meeting has focused on several key problems of endothelial cell pathobiology relevant to chronic kidney disease.

Animals↗

PubMed2006

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration.

Mitochondria are critical for cellular adenosine triphosphate (ATP) production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca(2+) levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. The techniques discussed include classic imaging techniques, such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multiphoton imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

Adenosine Triphosphate↗

PubMed2005

Tissue-specific accumulation of cadmium in subcellular compartments of eastern oysters Crassostrea virginica Gmelin (Bivalvia: Ostreidae).

Cadmium distribution was studied in different subcellular fractions of gill and hepatopancreas tissues of eastern oysters Crassostrea virginica. Oysters were exposed for up to 21 days to low sublethal Cd concentrations (25 microg L(-1)). Gill and hepatopancreas tissues were sampled and divided into organelle fractions and cytosol by differential centrifugation. Organelle content of different fractions was verified by activities of marker enzymes, citrate synthase and acid phosphatase for mitochondria and lysosomes, respectively. In both tissue types, there was a significant accumulation of cadmium in cytosol reaching 230-350 ng mg(-1) protein. Among organelles, mitochondria were the main target for Cd bioaccumulation in gills (250-300 ng mg(-1) protein), whereas in hepatopancreas tissues, the highest cadmium accumulation occurred in lysosomes (90-94 ng mg(-1) protein). Although 75-83% of total cadmium burden was associated with the cytosol reflecting high volume fraction of this compartment, Cd concentrations in organelle fractions reached levels that could cause dysfunction of mitochondria and lysosomes. Organ- and organelle-specific patterns of cadmium bioaccumulation support our previous in vivo studies, which showed adverse effects of cadmium exposures on mitochondrial oxidation in gills and on the lysosomal system of hepatopancreas. This may have important implications for the development of biomarkers of effect for heavy metals and for understanding the mechanisms of toxic effects of metals.

Acid Phosphatase↗

PubMed2005

Altered mitochondrial apparent affinity for ADP and impaired function of mitochondrial creatine kinase in gluteus medius of patients with hip osteoarthritis.

The cellular energy metabolism in human musculus gluteus medius (MGM) under normal conditions and hip osteoarthritis (OA) was explored. The functions of oxidative phosphorylation and energy transport systems were analyzed in permeabilized (skinned) muscle fibers by oxygraphy, in relation to myosin heavy chain (MHC) isoform distribution profile analyzed by SDS-PAGE, and to creatine kinase (CK) and adenylate kinase (AK) activities measured spectrophotometrically in the intact muscle. The results revealed high apparent Km for ADP in regulation of respiration that decreased after addition of creatine in MGM of traumatic patients (controls). OA was associated with increased sensitivity of mitochondrial respiration to ADP, decreased total activities of AK and CK with major reduction in mi-CK fraction, and attenuated effect of creatine on apparent Km for ADP compared with control group. It also included a complete loss of type II fibers in a subgroup of patients with the severest disease grade. It is concluded that energy metabolism in MGM cells is organized into functional complexes of mitochondria and ATPases. It is suggested that because of degenerative remodeling occurring during development of OA, these complexes become structurally and functionally impaired, which results in increased access of exogenous ADP to mitochondria and dysfunction of CK-phosphotransfer system.

Adenosine Diphosphate↗

PubMed1990

[Experimental studies on the changes of mitochondrial membrane phospholipids during cerebral ischemia and recirculation].

Changes of brain mitochondrial phospholipids during cerebral ischemia and recirculation were experimentally studied in a rat 4-vessel occlusion model, to explore the relation between changes of mitochondrial phospholipids and dysfunction of mitochondria. Respiratory functions, activities of respiratory enzymes (cytochrome c oxidase, F0F1-ATPase) were analyzed after 30 and 60 minutes of ischemia, and after 30 minutes of recirculation following each ischemic period. Activities of respiratory functions and respiratory enzymes decreased progressively during ischemia, which recovered completely after recirculation following 30 minutes of ischemia, while only partial recovery was observed after recirculation following 60 minutes of ischemia. In phospholipid analyses, contents of phospholipid classes tended to decrease time-dependently during ischemia, and compositions of polyunsaturated fatty acids (PUFA) such as arachidonic acid (20:4) and docosahexaenoic acid (22:6) were decreased preferentially. In recirculation, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) showed recovery of contents of phospholipids and compositions of PUFA after recirculation following 30 minutes of ischemia, while further decrease of contents of phospholipids and compositions of PUFA were observed after recirculation following 60 minutes of ischemia, especially in CL. On the other hand, progressive degradation of phospholipids occurred after recirculation following both 30 and 60 minutes of ischemia in phosphatidylserine and phosphatidylinositol. Changes of major phospholipid classes such as PC, PE, and CL correlated with the changes of mitochondrial respiratory functions and activities of respiratory enzymes. In conclusion, changes of mitochondrial membrane phospholipids appear to affect the integrity of cellular energy metabolism via mitochondrial dysfunction during cerebral ischemia and recirculation.

Animals↗

PubMed1999

Mitochondrial-nuclear interactions and lifespan control in fungi.

In fungi, mitochondrial-nuclear interactions are part of a complex molecular network involved in the control of aging processes. The generation of reactive oxygen species at the mitochondrial respiratory chain plays a major role in this network. Mitochondrial DNA instabilities, which are under the control of nuclear genes, affect the generation of reactive oxygen species and modulate the rate of aging. As mitochondria become dysfunctional, they transduce signals to the nucleus and induce the expression of a set of nuclear genes, a process termed retrograde regulation. Molecular data are emerging which suggest that retrograde regulation is involved in lifespan control.

Aging↗

PubMed2005

Propofol specifically inhibits mitochondrial membrane potential but not complex I NADH dehydrogenase activity, thus reducing cellular ATP biosynthesis and migration of macrophages.

Propofol is a widely used intravenous anesthetic agent. Our previous study showed that a therapeutic concentration of propofol can modulate macrophage functions. Mitochondria play critical roles in the maintenance of macrophage activities. This study attempted to evaluate further the effects of mitochondria on the propofol-induced suppression of macrophage functions using mouse macrophage-like Raw 264.7 cells as the experimental model. Macrophages were exposed to a clinically relevant concentration of propofol for 1, 6, and 24 h. Analysis by the Trypan blue exclusion method revealed that propofol was not cytotoxic to macrophages. Exposure of macrophages to propofol did not affect mitochondrial NADH dehydrogenase activity of complex I. However, analysis of flow cytometry showed that propofol significantly decreased the mitochondrial membrane potential of macrophages. Cellular levels of ATP in macrophages were significantly reduced after propofol administration. In parallel with the dysfunction of mitochondria, the chemotactic analysis showed that exposure to propofol significantly inhibited the migration of macrophages. This study shows that a therapeutic concentration of propofol can specifically reduce the mitochondrial membrane potential, but there is no such effect on complex I NADH dehydrogenase activity. Modulation of the mitochondrial membrane potential may decrease the biosynthesis of cellular ATP and thus reduce the chemotactic activity of macrophages. This study provides in vitro data to validate mitochondrial dysfunction as a possible critical cause for propofol-induced immunosuppression of macrophage functions.

Adenosine Triphosphate↗

PubMed2002

Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization.

Mitochondrial functional and structural impairment and generation of oxidative stress have been implicated in aging, various diseases and chemotherapies. This study analyzed azidothymidine (AZT)-caused failures in mitochondrial functions, in redox regulation and activation of the HIV-1 gene expression. We monitored intracellular concentrations of ATP and glutathione (GSH) as the indicators of energy production and redox conditions, respectively, during the time-course experiments with U937 and MOLT4 human lymphoid cells in the presence of AZT (0.05 mg x mL(-1)) or H(2)O(2) (0.01 mm) for 15-25 days. Mitochondrial DNA integrity and NF-kappa B-driven HIV-1 promoter activity were also assessed. ATP concentration began to decrease within several days after exposure to AZT or H(2)O(2), and the decrease continued to reach 30-40% of the normal level. However, decline of GSH was detectable after a retention period for at least 5-6 days, and progressed likewise. PCR analyses found that mitochondrial DNA destruction occurred when the ATP and GSH depletion had progressed, detecting a difference in the deletion pattern between AZT and H(2)O(2)-treated cells. The GSH decrease coincided with HIV-1 promoter sensitization detected by enhanced DNA binding ability of NF-kappa B and induction of the gene expression upon H(2)O(2)-rechallenge. Our results suggest that, in the process of AIDS myopathy development, AZT or oxidative agents directly impair the energy-producing system of mitochondria, causing dysfunction of cellular redox control, which eventually leads to loss of the mitochondrial DNA integrity. The mechanism of cellular redox condition-mediated NF-kappa B activation is discussed.

Adenosine Triphosphate↗

PubMed2001

ATP synthase activity in ovine ceroid lipofuscinosis [OCL6].

We measured ATP synthase activities in mitochondria isolated from livers of lambs with ceroid lipofuscinosis (OCL6) and compared them with those from similar isolations from obligate heterozygous and control lambs. Addition of excess Ca2+ to the incubation mixture resulted in an up-regulation of activity in mitochondria from control lambs but down-regulation in those from OCL6 affected lambs. The mean change in activity with Ca2+ for heterozygous animals was midway between those from control and affected groups being significantly different from control but not from affected. The change in ATP synthase activity to added Ca2+ was also measured in isolated mitochondria from affected and control lambs from 3 days to 25 months of age. As above, there was down-regulation to the addition of Ca2+ in affected lambs. There was a fall in percentage change to Ca2+ with age in both affected and control lambs. This was not significantly different in affected lambs indicating it was not associated with the stage of disease. The above in vitro results, if extrapolated to neurons in vivo, imply a potential dysfunction of mitochondria in OCL6 lambs that could lead to calcium mediated neurotoxicity and neuron death due to production of free radicals as implicit in the energy-linked excitotoxic hypothesis.

Animals↗