Oxidative Stress and Mitochondrial Dysfunction in Neurodegeneration of Transmissible Spongiform Encephalopathies (TSEs)
ABSTRACT Transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders that are invariably fatal in humans and animals. An important component of the infectious agent is a glyco-protein, termed PrPSc, which is derived from a normal cellular protein, termed PrPc. The pathogenic mechanisms of TSEs are not clear, but several factors such as oxidative stress and mitochondrial dysfunction have been reported to be involved. In the current review, we will present data that supports a role for oxidative stress and mitochondrial dysfunction in the induction of these diseases. We will discuss the pathways whereby oxidative stress and mitochondrial dysfunction could lead to neuronal damage and the clinical manifestations of TSE diseases.
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ABSTRACT: Mitochondria contain a sophisticated system for transporting Ca2+. The existence of a uniporter and of both Na+-dependent and -independent efflux mechanisms has been known for years. Recently, a new mechanism, called the RaM, which seems adapted for sequestering Ca2+ from physiological transients or pulses has been discovered. The RaM shows a conductivity at the beginning of a Ca2+ pulse that is much higher than the conductivity of the uniporter. This conductivity decreases very rapidly following the increase in [Ca2+] outside the mitochondria. This decrease in the Ca2+ conductivity of the RaM is associated with binding of Ca2+ to an external regulatory site. When liver mitochondria are exposed to a sequence of pulses, uptake of labeled Ca2+ via the RaM appears additive between pulses. Ruthenium red inhibits the RaM in liver mitochondria but much larger amounts are required than for inhibition of the mitochondrial Ca2+ uniporter. Spermine, ATP and GTP increase Ca2+ uptake via the RaM. Maximum uptake via the RaM from a single Ca2+ pulse in the physiological range has been observed to be approximately 7 nmole/mg protein, suggesting that Ca2+ uptake via the RaM and uniporter from physiological pulses may be sufficient to activate the Ca2+-sensitive metabolic reactions in the mitochondrial matrix which increase the rate of ATP production. RaM-mediated Ca2+ uptake has also been observed in heart mitochondria. Evidence for Ca2+ uptake into the mitochondria in a variety of tissues described in the literature is reviewed for evidence of participation of the RaM in this uptake. Possible ways in which the differences in transport via the RaM and the uniporter may be used to differentiate between metabolic and apoptotic signaling are discussed.Biochimica et Biophysica Acta 09/1998; 1366(1-2):5-15. · 4.66 Impact Factor
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ABSTRACT: Mitochondria are strategically localized at sites of Ca2+ release, such that increases in cytosolic free Ca2+ ([Ca2+]c) from either internal Ca2+ stores or Ca2+ influx across the plasma membrane can be rapidly transported into the mitochondrial matrix. The consequent elevation in mitochondrial Ca2+ ([Ca2+]m) stimulates the Ca2+-sensitive intramitochondrial dehydrogenases, resulting in elevation of NAD(P)H. The preferential coupling between increases in [Ca2+]c and [Ca2+]m is one proposed mechanism to coordinate mitochondrial ATP production with cellular energy demand. In liver cells, hormones that act through the second messenger inositol 1,4, 5-trisphosphate (IP3) generate oscillatory [Ca2+]c signals, which result from a periodic Ca2+- and IP3-mediated activation/deactivation of intracellular Ca2+ release channels. The [Ca2+]c spiking frequency increases with agonist dose, whereas the amplitude of each [Ca2+]c spike is constant. This frequency modulation of [Ca2+]c spiking encodes the signal from the extracellular agonist, which is then decoded by the internal Ca2+-sensitive proteins such as the Ca2+-sensitive intramitochondrial dehydrogenases. Our studies have investigated the relationship between IP3-dependent [Ca2+]c signals and [Ca2+]m in primary cultured hepatocytes. In addition, the changes in cellular [Ca2+] levels have been correlated with the regulation of intramitochondrial NAD(P)H levels, pyruvate dehydrogenase activity and the magnitude of the mitochondrial proton motive force.Biochimica et Biophysica Acta 09/1998; 1366(1-2):17-32. · 4.66 Impact Factor
Article: Mitochondrial disorders.[Show abstract] [Hide abstract]
ABSTRACT: We present here a discussion on the most relevant recent publications on mitochondrial disease. In addition to many papers concerning the description of the genotype-to-phenotype correlations in mitochondrial DNA-related disorders, this very broad area of neurogenetics includes a number of novel observations on the basic aspects of mitochondrial biogenesis that can be relevant in explaining the molecular mechanisms of mitochondrial abnormalities. The completion of the human genome project and the wealth of knowledge gained on the genetics of oxidative phosphorylation in yeast have promoted a substantial acceleration in the discovery of a remarkable number of nuclear genes associated with specific mitochondrial disorders. A further development of these contributions has been the generation of several cellular and animal models of disease that can now be exploited for testing both pathogenetic hypotheses and therapeutic strategies. Most of the latter are based on the use of chemical compounds aimed at reducing the negative impact of mitochondrial defects on both energy production and generation of reactive oxygen species. The first successful attempts for gene therapy of some mitochondrial diseases have recently been achieved and will hopefully increase in the near future.Rinsho shinkeigaku = Clinical neurology 01/1984; 23(12):1046-55.