Antioxidants, Oxidative Damage and Oxygen Deprivation Stress: a Review

Publisher Summary This chapter describes the present state of the studies of the molten globule state and its role in protein folding and physiological processes Recent data on the intermediates (equilibrium and kinetic), focusing attention on the molten globule state are discussed in the chapter The molten globule has a native-like overall architecture (folding pattern) without including the rigid packing of side chains It is separated by first-order phase transitions from both the native and the unfolded states and represents a third thermodynamic state of protein molecules It is a universal kinetic intermediate in protein folding; the structure of this intermediate is similar to the structure of the equilibrium molten globule It is predicted and confirmed experimentally that the molten globule state can exist in a living cell and plays an important role in a number of physiological processes

Molten globule and protein folding.

Mitochondria import many hundreds of different proteins that are encoded by nuclear genes These proteins are targeted to the mitochondria, translocated through the mitochondrial membranes, and sorted to the different mitochondrial subcompartments Separate translocases in the mitochondrial outer membrane (TOM complex) and in the inner membrane (TIM complex) facilitate recognition of preproteins and transport across the two membranes Factors in the cytosol assist in targeting of preproteins Protein components in the matrix partake in energetically driving translocation in a reaction that depends on the membrane potential and matrix-ATP Molecular chaperones in the matrix exert multiple functions in translocation, sorting, folding, and assembly of newly imported proteins

Protein import into mitochondria.

Lipids of mitochondria

The quest to disentangle the aetiopathogenesis of Parkinson's disease has been heavily influenced by the genes associated with the disease. The alpha-synuclein-centric theory of protein aggregation with the adjunct of parkin-driven proteasome deregulation has, in recent years, been complemented by the discovery and increasing knowledge of the functions of DJ1, PINK1 and OMI/HTRA2, which are all associated with the mitochondria and have been implicated in cellular protection against oxidative damage. We critically review how these genes fit into and enhance our understanding of the role of mitochondrial dysfunction in Parkinson's disease, and consider how oxidative stress might be a potential unifying factor in the aetiopathogenesis of the disease.

Expanding insights of mitochondrial dysfunction in Parkinson's disease

Autophagy is a regulated process for the degradation of cellular components that has been well conserved in eukaryotic cells. The discovery of autophagy-regulating proteins in yeast has been important in understanding this process. Although many parallels exist between fungi and mammals in the regulation and execution of autophagy, there are some important differences. The pre-autophagosomal structure found in yeast has not been identified in mammals, and it seems that there may be multiple origins for autophagosomes, including endoplasmic reticulum, plasma membrane and mitochondrial outer membrane. The maturation of the phagophore is largely dependent on 5’-AMP activated protein kinase and other factors that lead to the dephosphorylation of mammalian target of rapamycin. Once the process is initiated, the mammalian phagophore elongates and matures into an autophagosome by processes that are similar to those in yeast. Cargo selection is dependent on the ubiquitin conjugation of protein aggregates and organelles and recognition of these conjugates by autophagosomal receptors. Lysosomal degradation of cargo produces metabolites that can be recycled during stress. Autophagy is an important cellular safeguard during starvation in all eukaryotes; however, it may have more complicated, tissue specific roles in mammals. With certain exceptions, autophagy seems to be cytoprotective, and defects in the process have been associated with human disease.

Autophagy in mammalian cells

Ubiquitin is involved in the in vitro insertion of monoamine oxidase B into mitochondrial outer membranes.

Clorgyline, a selective MAO-A inhibitor, increased (5 times) rat pineal melatonin and N-acetyl-serotonin (NAS) content, and decreased 5-HIAA level by 80% Deprenyl, a selective MAO-B inhibitor, did not change melatonin or other pineal indoles content The data obtained show that inhibition of MAO-A but not B enzyme is responsible for pineal melatonin increase caused by MAO inhibitors

Roy B. McCauley

Papers

Autophagy in mammalian cells

Ubiquitin is involved in the in vitro insertion of monoamine oxidase B into mitochondrial outer membranes.

Selective inhibition of MAO-A but not MAO-B activity increases rat pineal melatonin.

The insertion of monoamine oxidase A into the outer membrane of rat liver mitochondria.

Activation of Src protein tyrosine kinase plays an essential role in urocortin-mediated cardioprotection