Mitochondria

Mitochondrial function. Cell organelles playing a major role in aging are mitochondria, due to their central role in energy supply, as major source of oxidative stress, and as critical regulators of apoptosis. During evolution, the brain developed specific mechanisms to compensate oxidative stress, which could be specifically activated by nutrients, such as polyunsaturated fatty acids, Mediterranean plant and berry extracts as well as isolated secondary plant compounds, such as hydroxytyrosol, or curcumin. 

Mitochondria – key organelles for energy supply and cell death

Increasing evidence suggests that mitochondrial dysfunction plays an important role not only in brain aging but also in the pathogenesis of neurodegenerative diseases including AD. Mitochondria are complex, network forming organelles, involved in different metabolic pathways, e.g. citric acid cycle (TCA), energy transformation, amino acid metabolism and urea cycle. Mitochondria consist of inner and outer membranes composed of phospholipid bilayers and proteins. The inner mitochondrial membrane harbors the proteins of the electron transfer system (ETS), responsible for oxidative phosphorylation. The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway producing energy in form of ATP by consuming oxygen. Electrons are transferred through the complexes of the mitochondrial respiration chain and simultaneously, an electrochemical proton gradient is build across the inner mitochondrial membrane generating the proton-motive force the production of ATP. 

Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial mass, amount of respiratory enzymes or changes in enzyme activities. A reduction in mitochondrial content or lowered ETS results in a general limitation of cellular energy production. Dysfunction of single complexes of the respiratory system are frequently accompanied by deleterious side effects, such as loss of mitochondrial membrane potential (MMP) and subsequently decreased ATP levels, but also production of reactive oxygen species (ROS). 

Mitochondria

Beside enzymatically produced ROS by NADPH oxidases, cytochrome P450-dependent oxygenases, and xanthine dehydrogenases, mitochondria are regarded as the primary site of ROS production within cells. The ETS constantly generates low physiological levels of ROS, which trigger various defense mechanisms, i.e anti-oxidative molecules (e.g. glutathione or vitamin E) and antioxidant enzymes (e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase and glutathione reductase). Furthermore, slight uncoupling of the ETC, for instance by uncoupling proteins, is one possibility to achieve a reduction in ROS production. Functional failure of this system can lead to deleterious effects, which might exaggerate consequence of mitochondrial dysfunction. Mitochondria are often considered as both the initiator and the first target of oxidative stress. Insufficient defense mechanisms and excessive ROS production (e.g as superoxide anions) can lead to cell damage. The major sources of superoxide anions are redox centers of complex I and III of the ETS and different mitochondrial flavoproteins. Superoxide is a rather weak radical, but it is the precursor of various, potentially more toxic  ROS. Its transformation into hydrogen peroxide, hydroxyl radicals as well as its participation in the formation of peroxynitrate creates strong oxidants. 

Proteins of the OXPHOS system and lipids are key targets of the deleterious effects of ROS and might lead to membrane depolarization and subsequently impaired mitochondrial function. For example, oxidative damage of omega-3 polyunsaturated fatty acids (PUFA) in the inner mitochondrial membrane has been shown to result in loss of MMP, representing one early hallmark of apoptosis. Mitochondria act as signal-integrating organelles in the on-set of the intrinsic apoptotic pathway. Mitochondrial outer membrane permeabilization and permeability transition result both in the release of pro-apoptotic proteins which in turn activate caspases and further down-stream cell death mechanisms.

Dysfunction of single mitochondrial enzyme complexes, ROS production, mitochondrial permeability transition pore opening (mPTP), elevated apoptosis, but also structural alterations and a diminished mitochondrial content play a role in brain aging and are believed to be crucial for the onset and progression of neurodegenerative diseases.


© Prof. Dr. Gunter P. Eckert 2018