Mitochondrial complex 1 activity measured by spectrophotometry is reduced across all brain regions in ageing and more specifically in neurodegeneration

Mitochondrial function, in particular complex 1 of the electron transport chain (ETC), has been shown to decrease during normal ageing and in neurodegenerative disease. However, there is some debate concerning which area of the brain has the greatest complex 1 activity. It is important to identify the pattern of activity in order to be able to gauge the effect of age or disease related changes. We determined complex 1 activity spectrophotometrically in the cortex, brainstem and cerebellum of middle aged mice (70–71 weeks), a cerebellar ataxic neurodegeneration model (pcd5J) and young wild type controls. We share our updated protocol on the measurements of complex1 activity and find that mitochondrial fractions isolated from frozen tissues can be measured for robust activity. We show that complex 1 activity is clearly highest in the cortex when compared with brainstem and cerebellum (p<0.003). Cerebellum and brainstem mitochondria exhibit similar levels of complex 1 activity in wild type brains. In the aged brain we see similar levels of complex 1 activity in all three-brain regions. The specific activity of complex 1 measured in the aged cortex is significantly decreased when compared with controls (p<0.0001). Both the cerebellum and brainstem mitochondria also show significantly reduced activity with ageing (p<0.05). The mouse model of ataxia predictably has a lower complex 1 activity in the cerebellum, and although reductions are measured in the cortex and brain stem, the remaining activity is higher than in the aged brains. We present clear evidence that complex 1 activity decreases across the brain with age and much more specifically in the cerebellum of the pcd5j mouse. Mitochondrial impairment can be a region specific phenomenon in disease, but in ageing appears to affect the entire brain, abolishing the pattern of higher activity in cortical regions

Do Statins Influence the Activity of c-fos Gene Following Transient Forebrain Ischaemia in the Adult Rat Hippocampus?

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been associated with stroke prevention. This stroke prevention appears to occur apart from cholesterol lowering effects. A number of mechanisms have been postulated for this prevention. The aim of our study was to investigate the effect of simvastatin on the c-fos gene activity and its relation to delayed neuronal death in CA1 region of hippocampus following transient forebrain ischemia in the adult rat hippocampus. A total of 17 male Wistar albino rats were used in this study. The animals were divided into three groups: 5 sham-operated animals; 6 ischemised rats without statin pre-treatment and 6 ischemised rats with statin pre-treatment. We used simvastatin at the dose of 20 mg/kg during 14 days prior to the ischemic attack. Fifteen min long transient forebrain ischemia was induced by the four-vessel occlusion. Two and a half h reperfusion was used for the c-Fos activity detection using immunostaining and 72 h reperfusion was used for the determination of neurons surviving using haematoxylin/eosin staining. The average neuronal density in the CA1 region of hippocampus in the sham-operated rats, in ischemised rats without pre-treatment and in ischemised rats with statin pre-treatment was 47.03 ± 3.09/0,025 mm2, 9.05 ± 2.46/0,025 mm2 and 16.45 ± 2.78/025 mm2, respectively. A significant neuroprotective effect was observed in the pre-treated ischemic group (P 2, 28.2 ± 2.053/025 mm2, 30.3 ± 4.816/025 mm2, respectively. A highly significant difference in c-Fos positivity (P P > 0.05). These findings indicate that simvastatin provides protection against CA1 hypoxic neuronal injury, which is independent of c-fos activation. We can conclude that simvastatin neuroprotection may be mediated by multiple mechanisms as can be expected based on its pleiotropic effects

The Interplay Between Respiratory Supercomplexes and ROS in Aging

Significance: The molecular mechanism of aging is still vigorously debated, although a general consensus exists that mitochondria are significantly involved in this process. However, the previously postulated role of mitochondrial-derived reactive oxygen species (ROS) as the damaging agents inducing functional loss in aging has fallen out of favor in the recent past. In this review, we critically examine the role of ROS in aging in the light of recent advances on the relationship between mitochondrial structure and function. Recent Advances: The functional mitochondrial respiratory chain is now recognized as a reflection of the dynamic association of respiratory complexes in the form of supercomplexes (SCs). Besides providing kinetic advantage (channeling), SCs control ROS generation by the respiratory chain, thus providing a means to regulate ROS levels in the cell. Depending on their concentration, these ROS are either physiological signals essential for the life of the cell or toxic species that damage cell structure and functions. Critical Issues: We propose that under physiological conditions the dynamic nature of SCs reversibly controls the generation of ROS as signals involved in mitochondrial- nuclear communication. During aging, there is a progressive loss of control of ROS generation so that their production is irreversibly enhanced, inducing a vicious circle in which signaling is altered and structural damage takes place. Future Directions: A better understanding on the forces affecting SC association would allow the manipulation of ROS generation, directing these species to their physiological signaling role