Updates of Mitochondrial Dysfunction in Neurodegenerative Disorders

Abstract

Mitochondria play a central role in energy metabolism of cells. They usually provide most of the ATP by oxidative phosphorylation. Amajor consequence of the architecture of mitochondria is the impermeability of the inner membrane that facilitates the generation of a proton gradient, called the proton motive force. The oxidative processes cells use to degrade fuel molecules yield NADH and FADH2 which are used as electron donors for the electron transport chain. The components of the chain are located in the inner mitochondrial membrane and include four complexes and some electron carriers. With the current explosion of knowledge on the role of mitochondrial dysfunction in the genesis of various human disease states, there is an increased interest in targeting mitochondrial processes, pathways, and proteins for drug discovery efforts in cancer and cardiovascular, metabolic, and central nervous system diseases, the latter including neurodegenerative disorders. A mitochondrial dysfunction and oxidative damage play role s in the pathogenesis of numerous disorders, e.g. PD, AD, HD, ALS, Wilson's disease, Friedreich's ataxia , multiple sclerosis and a number of inherited disorders of the mitochondrial genome, the mitochondrial encephalomyopathies (e.g., Leber's disease with optic a trophy and dystonia, MELA S, MERR F, Leigh' s disease , Kearns –Sayre syndrome). The list of mitochondria related diseases is growing rapidly: cancer, heart failure, diabetes, obesity, ischemia-reperfusion injury, atherosclerosis, certain liver diseases and asbestosis. They all share the common features of disturbances of the mitochondrial Ca2+, ATP or ROS metabolism There is clear evidence that the deficiency of frataxin in Friedreich’s Ataxia results in increased mitochondrial iron, decreased respiratory chain function and elevated oxidative stress. However, current data suggests that the iron accumulation may be a relatively late event in the disease process, and a primary cause of the disease may well involve abnormal Fe-S synthesis. Frataxin has been suggested to act as a mitochondrial store of bio-available iron and/or delivery of iron for Fe-S centre synthesis. The resultant dysfunction of respiratory chain complexes I-III and aconitase will lead to a decrease in ATP synthesis and an increase in free radical production from the inhibited respiratory chain. Mitochondrial dysfunction plays a critical role in mutant SOD1 mediated familial ALS. Various aspects of the underlying mechanisms as well as functional consequences of mitochondrial dysfunction include association of mutant SOD1 aggregates with mitochondria, abnormal mitochondrial morphology, impaired mitochondrial bioenergetics, loss of mitochondrial membrane potential, reduced mitochondrial calcium buffering capacity and disrupted calcium homestasis, impaired axonal transport of mitochondria, and potential imbalance of mitochondrial fission and fusion. Numerous studies report the involvement of ROS in cell death after cerebral ischemia. ROS contribute not only to injury of macromolecules such as lipids, proteins, and DNA, but also to transduction of apoptotic signals. Mitochondrial dysfunctions occur as a consequence of cerebral ischemia and promote ischemia induced neuronal cell death, especially the intrinsic pathway of apoptotic cell death. Conversely, endogenous protective pathways exist to counteract these detrimental effects induced by ischemia including mitochondria proteins UCP2 and SOD2, which are all regulated by PGC-1α. Therefore, mitochondria can be considered as a target for potential neuroprotective strategies in cerebral ischemia. Future studies of these cell death /survival mechanisms subsequent to ischemic attack may provide unique information regarding molecular targets for therapeutic strategies in clinical stroke. Protection of the mitochondria from bioenergetics failure and oxidative/nitrosative stress resulting in apoptosis in the ischemic tissue may open a new vista to the development of more effective neuroprotective strategies against ischemia-induced brain damage.