Mechanistic Analysis Of Biguanide Induced Inhibition Of Oxidative Phosphorylation

One of the fascinating things I have learned in Cell Biology was how the uncoupling ATP synthesis works in the mitochondria, and we now use this to create DNP, a weight loss drug. We have 37 trillion cells in our body, and mitochondria is one of the many organelles in our cells, the basic unit of all living things. Amazingly, the discovering the mechanisms of ATP synthesis in that tiny compartment has changed the lives of thousands of people through pharmaceuticals.

There is still controversy between magnetic nuclear resonance data and experimentally demonstrated data on chemical property of polyenes towards binding of ergosterol [M. Baginski et.al, 1997] [J. Milhaud et.al. 2002]. Some research suggested that polyene drugs are able to induce an oxidative stress (particularly in C. albicans [M. A. Ghannoum, 1999] [R. A. Akins, 2005] as well as their activity seems to be reduced in hypoxic conditions [P. A. Warn et al. 2004].

Under normal condition, ROS production in the brain is balanced by the endogenous enzymatic and non-enzymatic anti-oxidative mechanisms. The enzymes include superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase. SOD catalyzes dismutation of superoxide to hydrogen peroxide, providing the first line against ROS damage [46, 70]. GPX and catalase further metabolize hydrogen peroxide to water and oxygen [71]. In the process, reduced glutathione (GSH) is oxidized to oxidized glutathione (GSSG) and it can be recycled by the NADPH-dependent GSSG reductase [72]. Non-enzymatic endogenous anti-oxidative small molecules also play very important roles in defending against oxidative stress, especially in extracellular space that the enzymes are absent or in very low levels [73]. Small-molecule anti-oxidant can be water-soluble or lipid-soluble, these molecules include glutathione, vitamin E and C (inhibits

Many animal studies have shown that lead is capable of causing oxidative stress in many organs (Patra et al., 2001). Toxicity of lead is mainly attributed to the induction of oxidative stress by disruption of the pro-oxidant/anti-oxidant balance, elevation of reactive oxygen and nitrogen species (ROS and RNS, respectively) such as superoxide radicals, hydrogen peroxide, hydroxyl radicals and lipid peroxides, and nitric oxide (Kumar and Reddy, 2012). Currently, N-acetyl-L-cysteine (NAC), derives from L-Cysteine and the precursor of glutathione (GSH), is a well-established cyto-protective drug against drugs induced hepatotoxicity and nephrotoxicity (Whyte et al., 2007; Akbulut et al., 2014), where it exerts antioxidant properties. L-Cysteine was utilized as a chelator of heavy metal to conserve against oxidative stress and inhibit damage to cells and tissues. L-cysteine, a sulfur-containing amino acid, is a nutritionally occurring non-essential amino

Oxidants will affect mitochondrial redox status and may cause extensive oxidative damage to proteins(Kalyanaraman et al .,2002). Furthermore, the mitochondrial transition pore can open releasing cytochrome c and possibly affecting mitochondrial function. Cytochrome c can activate cytosolic caspases to induce apoptosis. Doxorubicin may induce anti-apoptotic (Bcl-2, Bcl-XL) and pro-apoptotic (Bax, Bad) proteins. The Bcl-2 family of proteins regulates the release of cytochrome c . These include Bax, Bad, and Bid, which are pro-apoptotic proteins that favor cytochrome c release and Bcl-2 and Bcl-XL which are anti-apoptotic proteins that inhibit cytochrome c release . The mechanisms of how Bcl-2 family proteins regulate release of cytochrome c and apoptogenic factors are under investigation.

It functions as a strong uncoupling agent on liver cell mitochondria, and further alter cell metabolism by uncoupling oxidative phosphorylation and glycolysis. More specifically, Tamoxifen inhibits the activities of complex II+III (IC50 =15µM) and complex V (IC50 =8.1µM) [6] of the electron transport chain. The IC50 doses of tamoxifen in liver cell mitochondria agree with reported cytotoxic doses in MCF10A and the observed cytotoxic doses in this study, which further supports that the potential mechanism governing tamoxifen toxicity is due to its inhibition of this pathway.

Many physiological processes in the cells require the participation of both intra- and extra-mitochondrial enzyme reactions. A link between mitochondria and cytosol is provided by a group of proteins known as the mitochondrial carriers (MCs) family (Arco & Satrustegui, 2005; F. Palmieri, 2004). MCs comprise a family of about 40-50 proteins, depending on the organism, and provide the main communication between mitochondrial matrix and extra-mitochondrial spaces by transporting a wide range of metabolites, nucleotides and cofactors.

Specific Aim 2. To determine the mechanism of Cys106-sulfonate DJ-1 degradation in mitochondria in human primary alveolar type II (ATII) cells in emphysema in vitro.

The cell’s mitochondrial population is normally highly dynamic and exhibits variable turnover rates. The turnover process is accomplished by an actively regulated transcriptional network for mitochondrial replenishment that is coordinated with the degradation and elimination of senescent and damaged mitochondria by selective mitochondrial autophagy or mitophagy. Although mitochondria are constantly renewed, the ongoing rate of homeostatic QC processes in vivo is fairly low (Miwa et al., 2008) on the order of days, whereas in cells, it is more rapid (Hernandez et al., 2013). Mitochondrial turnover in the rat heart has an estimated half-life of roughly two weeks (Rabinowitz and Zak, 1975). Thus, for a typical cardiomyocyte under basal conditions (~1000 mitochondria), 1.5 mitochondria would be replaced each hour. Moreover, mitochondrial turnover may be regulated by the circadian clock as a number of OXPHOS enzymes show strong diurnal variation in expression. This may be related in part to the period of fasting during sleep; therefore mitochondrial turnover at night may be more active with a few percent of the mitochondrial population replaced each night. Mitochondrial turnover rates also vary with specific metabolic status of tissues, but can be greatly

Within the 2H88 complex II protein, an inhibitor was also discovery when they were analyzing the structure of it. The malate like intermediate, TEO, mentioned before was found to be an inactive suicide inhibitor. During normal functions, without the presence of TEO, FAD functions normally by grabs the hydrogen from Succinate and form FADH2. However, when TEO is present such inhibitor serves as a negative feedback (Shen, J.T.et. al. 2006). When too much Ubiquinone were produced, and not enough electrons are transferred fast enough to form ubiquinol, the excessive Ubiquinone can oxidize TEO to oxaloacetate (OAA) . OAA then inhibits succinate oxidation. TEO binds to FAD functions to inhibit in the form of Oxaloacetate the flavin protein

A team of researchers from Boston University, supervised by Thomas Tien, studied the mitochondrial function

Mitochondrion is considered the energy fuel of the cell. It is the primary site for the ATP production oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery system is mainly composed of five multisubunits complexes (complexes I–V), which are produced by mitochondrial genome. Mitochondrial electron transport chain (ETC) has several essential physiological roles, in which, it is the main source of ATP production in the cell, in addition, its constituent enzyme complexes are a major source of ROS generation. Previous studies tested the effect of A on the mitochondrial bioenergetics function, and have concluded that direct exposure to A leads to significant impairment in the functionality of mitochondrial electron transport

Pyranose 2-oxidase catalyzes the oxidation of aldopyranoses by using molecular oxygen as an electron acceptor to yield the corresponding keto-aldoses and hydrogen peroxide. This enzyme belongs to the Glucose-Methanol-Choline (GMC) oxidoreductase superfamily and contains flavin adenine dinucleotide (FAD) as a cofactor. P2O catalyzes regio-specific oxidation at the C2 position. Here, the hydride transfer reaction from glucose to oxidized flavin catalyzed by pyranose 2-oxidase (P2O) was investigated by density functional theory calculations and transient kinetics. Our findings suggest that the first step of the P2O reaction is a hydride transfer from C2 position of glucose to N5 of the flavin. Then, the proton abstraction occurs by the conserved

Second, they may oxidize signaling pathways directly. And third, ROS may target and modify transcription factors where the eventual effect may bring about change in gene expression. Furthermore, ROS activate MAPK signaling cascades which is central for mediating cellular responses to multiple stresses (Abouzari and fakheri, 2015). They do so through Calcium ion (Ca2+) (Price et al., 1994). Furthermore, key signaling proteins such as tyrosine phosphatase sense ROS directly through the oxidation of conserved cysteine residues (Xiong et al., 2002). On the other hand, ROS take part in redox cycling of cysteinyl thiols which is crucial to establish protein-protein and protein-DNA

The study of bioenergetics includes and not limited to study of biological membranes incurred in energy conversion and transfer. In particular, the study concentrates on structures acquired using X-ray craystallography, molecular mechanisms of the photosynthesis processes, bacteria respiration, mitochondrial, transport, motility and oxidative phosphorylation. Furthermore, areas of structural biology, spectroscopy, molecular modelling and biophysics of the system applications are not left out while studying the specific chemical process of a disease. Bioenergetics further spans in the biology of mitochondrial that embodies biomedicine, features of mitochondrial disorders and energy metabolism (Zheng et-al, 2010, p.519). Alzheimer’s disease, Parkinson’s disease, aging, cancer and diabetes are among the well-known neurodegenerative illnesses studied under bioenergetics and use of small molecule therapeutics.