Calcium buffering by mitochondria is important to neurons. Presynaptic mitochondria are responsible for clearing calcium for proper neurotransmitter release and can affect the rate of recovery from synaptic depression after moderate synaptic Crenolanib GIST activity [3]. Also, neurons have lipid membranes with high proportions of polyunsaturated fatty acids which are susceptible to oxidative damage by reactive oxygen species. Therefore, neuronal functioning relies heavily on the presence of healthy mitochondria, and consequently mitochondrial dysfunction is a fundamental part of neurodegeneration.

Impairment of the vital functions of the mitochondria broadly referred to as ��mitochondrial dysfunction�� causes the cell to take protection against stress by activating a multitiered defence system which involves not only the mitochondria but also other cellular machinery like the cytoplasmic ubiquitin proteasomal system (UPS), the autophagy process, part of the endoplasmic reticulum quality control machinery, and finally activation of programmed cell death as the last level of defence. This review summarises the response of the cellular quality control machinery to mitochondrial damage associated with neurodegenerative disease and the alterations caused to these cellular surveillance systems in common neurodegenerative disorders.2. Oxidative Stress and NeurodegenerationMitochondria are the main producers of endogenous reactive oxygen species. ROS are an inevitable by-product of oxidative phosphorylation.

Mitochondrial enzymes that generate ROS include the members of the electron-transport chain (ETC): complexes I, II, and III; tricarboxylic acid (TCA) cycle enzymes aconitase and ��-ketoglutarate dehydrogenase; pyruvate dehydrogenase; glycerol-3-phosphate dehydrogenase; dihydroorotate dehydrogenase; the monoamine oxidases; and cytochrome b5 reductase [1]. ROS levels in the mitochondrial matrix are determined by the proton gradient across the inner membrane, the efficiency of ATP production by the respiratory chain, and the ratio of the reduced to oxidised form of nicotinamide adenine dinucleotide (NADH/NAD+ ratio) [4]. ROS can cause oxidative damage to mitochondrial proteins, mutations in mitochondrial DNA (mtDNA), oxidation of lipids in the mitochondrial membranes, opening of the mitochondrial permeability transition pore, and release of proapoptotic molecules like cytochrome c from the mitochondria.

Excess ROS production and oxidative damage can operate in a vicious cycle where one can trigger the other. Mitochondria have antioxidants like glutathione and ��-tocopherol and enzymes like manganese Anacetrapib superoxide dismutase (MnSOD), catalase, and glutathione peroxidase to detoxify ROS. However, perturbation of the delicate balance between the antioxidant defence capacity and the ROS levels leads to oxidative stress and mitochondrial damage.