Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Abstract

For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

“…This can suggest that a decrease in complex I activity may be involved in the pathogenesis of the disease. These results are in agreement with previous studies that have also demonstrated mitochondrial impairment activity in related diseases, such as AD, PD, ALS and tauopathies [32,85,86,87,88]. Moreover, our group has previously reported a complex I deficiency in a patient with FTLD [22].…”

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…At the mitochondrial respiratory chain, the small amount of electron leakage (0.1% to 4%) induces one-electron reduction of oxygen, which results in relatively stable superoxide anion-a free radical with biologic toxicity. 172 Superoxide anion is generated at several mitochondrial sites such as complexes I and III, and this occurs readily during mitochondrial respiration at physiologic levels of neuronal activity. Specific genome mutations, for example, alter the electron transfer properties of respiratory chain complexes and result in abnormal high levels of superoxide anion.…”

“…Clinical examples are mitochondrial disorders (mitochondriopathies), arteriosclerosis, ageing, Alzheimer's disease, Parkinson's disease, and schizophrenia. 5,13,72,167,172,185 Indeed, experimental evidence suggests that fast-spiking interneurons have a key role in the (patho)physiologic processes underlying ageing, Alzheimer's disease, and schizophrenia. 165,183,[186][187][188] While recent studies yielded considerable insight into mitochondria and neuroenergetics during gamma oscillations, important features of interneurons, in particular, of fast-spiking interneurons, have been less defined.…”

Bcl-2 Phosphorylation Triggers Autophagy Switch and Reduces Mitochondrial Damage in Limb Remote Ischemic Conditioned Rats After Ischemic Stroke

“…Autophagy is a vital intracellular degradation pathway of macromolecules or damaged organelles for subsequent reuse, which helps to maintain intracellular homeostasis during starvation, malignancy, and neurodegeneration [9][10][11][12][13]. The phosphorylation of Bcl-2 at Ser70 has recently been reported to trigger the disruption of the Bcl-2/Beclin1 complex (a molecular switch for autophagy), which results in Beclin1 release and autophagosome formation [14].…”