Mitochondrial dysfunction in neurodegenerative disorders.

There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative disorders, such as Morbus Parkinson, FRDA (Friedreich's ataxia), ALS (amyotrophic lateral sclerosis), and temporal lobe epilepsy with Ammon's horn sclerosis. This evidence includes the direct genetic evidence of pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe epilepsy with Ammon's horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative disorders including ALS and temporal lobe epilepsy with Ammon's horn sclerosis. In the present study, we critically review the available data.

Mitochondrial complex I deficiency in the epileptic focus of patients with temporal lobe epilepsy.

Mitochondria are cellular organelles crucial for energy supply and calcium homeostasis in neuronal cells, and their dysfunction causes seizure activity in some rare human epilepsies. To directly test whether mitochondrial respiratory chain enzymes are abnormal in the most common form of chronic epilepsy, temporal lobe epilepsy (TLE), living human brain specimens from 57 epileptic patients and 2 nonepileptic controls were investigated. In TLE patients with a hippocampal epileptic focus, we demonstrated a specific deficiency of complex I of the mitochondrial respiratory chain in the hippocampal CA3 region. In contrast, TLE patients with a parahippocampal epileptic focus showed reduced complex I activity only in parahippocampal tissue. Inhibitor titrations of the maximal respiration rate of intact human brain slices revealed that the observed reduction in complex I activity is sufficient to affect the adenosine triphosphate production rate. The abnormal complex I activity in the hippocampal CA3 region was paralleled by increased succinate dehydrogenase staining of neurons and marked ultrastructural abnormalities of mitochondria. Therefore, mitochondrial dysfunction is suggested to be specific for the epileptic focus and may constitute a pathomechanism contributing to altered excitability and selective neuronal vulnerability in TLE.

Effects of cumene hydroperoxide on the Ca(2+)-induced Ca2+ efflux from mitochondria and on the viability of hepatoma cells.

Effects of cumene hydroperoxide on the Ca(2+)-induced Ca2+ efflux from mitochondria isolated from rat liver and Zaidelja hepatoma were compared. Cumene hydroperoxide at micromolar concentrations (0.3-10 microM) prevented the closing of the permeability transition pore in the inner mitochondrial membrane and, therefore, potentiated the Ca(2+)-induced Ca2+ efflux. This response was 10-100 times greater in hepatoma mitochondria than in rat liver mitochondria. Micromolar concentrations of cumene hydroperoxide induced the death of the hepatoma cells in vitro.

Calcium binding to polypeptides of rat liver and Zajdela hepatoma mitochondrial inner membranes.

Composition and amount of 45Ca2+-binding proteins in the inner membrane fraction of rat liver and Zajdela hepatoma mitochondria were determined. In the inner membrane of liver mitochondria, three major 45Ca2+-binding polypeptides: a protein of approximately 130 kDa (carbamoyl-phosphate synthetase), a glycoprotein of 43-44 kDa (previously considered as the calcium uniporter), and 29-30 kDa protein were found. These components were absent (130 kDa component) or relatively reduced (43-44 kDa and 29-30 kDa components) in the inner membrane of hepatoma mitochondria. Previously unknown low molecular mass polypeptides, having very high Ca2+-binding ability, were found in the inner membrane of hepatoma mitochondria. One of them might be the natural Ca2+-binding inhibitor of H+-ATPase.

Polypeptide composition of submitochondrial fractions of normal liver tissue and Zajdela hepatoma.

The polypeptide composition of liver and Zajdela hepatoma mitochondria is compared. Polypeptides of mitochondria and submitochondrial fractions (the outer and the inner mitochondrial membranes, the intermembrane and the matrix spaces of mitochondria) were separated by electrophoresis in polyacrylamide gel. The percentage content of each polypeptide was evaluated after scanning gels using a differential spectrophotometer-densitometer. Significant changes of several proteins of the hepatoma mitochondria and submitochondrial fractions as compared with normal liver preparations have been found.