RESUMEN
Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.
Asunto(s)
Enfermedades Mitocondriales/etiología , Enfermedades Neurodegenerativas/complicaciones , Estrés Oxidativo/fisiología , Animales , HumanosRESUMEN
In metabolic diseases such as obesity, metabolic syndrome and type II diabetes, the over-expression of uncoupling proteins (UCPs) in a response to increased reactive oxygen species (ROS) generation by mitochondrial respiratory complexes, and to the excess of free fatty acid (FFA) supply from adipose tissue, may protect cells from oxidative stress, lipotoxicity and in turn from death. UCPs by reducing superoxide anion and H2O2 generation trigger several signals to cell for their adaptation to the lipotoxic microenvironment. In mitochondria, a decrease of cytochrome c (cyt c) and proapoptotic protein release promotes cell survival and proliferation. The altered lipid metabolism also affects cardiolipin susceptibility to the peroxidation, a process involved in the dissociation of cyt c from mitochondrial inner membrane and its release, a key step of apoptosis. Therefore, UCPs by attenuating ROS generation and lipotoxicity may downregulate programmed cell death, a well-known physiological process controlling cell proliferation contributing to uncontrolled cell proliferation and tumorigenesis. In addition, tumor cells over-expressed UCPs, by inhibiting ROS generation acquire resistance to death during pharmacological treatment with oxidative stress drug inducers. Therefore, the aim of this review is to discuss recent findings regarding the role that UCPs play in cell survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote cell proliferation.
Asunto(s)
Carcinogénesis/patología , Proliferación Celular , Enfermedades Metabólicas/fisiopatología , Proteínas Desacopladoras Mitocondriales/metabolismo , Neoplasias/fisiopatología , Animales , Carcinogénesis/metabolismo , HumanosRESUMEN
The chemotherapeutic isothiocyanate sulforaphane (SFN) was early linked to anticarcinogenic and antiproliferative activities. Soon after, this compound, derived from cruciferous vegetables, became an excellent and useful trial for anti-cancer research in experimental models including growth tumor, metastasis, and angiogenesis. Many subsequent reports showed modifications in mitochondrial signaling, functionality, and integrity induced by SFN. When cytoprotective effects were found in toxic and ischemic insult models, seemingly contradictory behaviors of SFN were discovered: SFN was inducing deleterious changes in cancer cell mitochondria that eventually would carry the cell to death via apoptosis and also was protecting noncancer cell mitochondria against oxidative challenge, which prevented cell death. In both cases, SFN exhibited effects on mitochondrial redox balance and phase II enzyme expression, mitochondrial membrane potential, expression of the family of B cell lymphoma 2 homologs, regulation of proapoptotic proteins released from mitochondria, activation/inactivation of caspases, mitochondrial respiratory complex activities, oxygen consumption and bioenergetics, mitochondrial permeability transition pore opening, and modulation of some kinase pathways. With the ultimate findings related to the induction of mitochondrial biogenesis by SFN, it could be considered that SFN has effects on mitochondrial dynamics that explain some divergent points. In this review, we list the reports involving effects on mitochondrial modulation by SFN in anti-cancer models as well as in cytoprotective models against oxidative damage. We also attempt to integrate the data into a mechanism explaining the various effects of SFN on mitochondrial function in only one concept, taking into account mitochondrial biogenesis and dynamics and making a comparison with the theory of reactive oxygen species threshold of cell death. Our interest is to achieve a complete view of cancer and protective therapies based on SFN that can be extended to other chemotherapeutic compounds with similar characteristics. The work needed to test this hypothesis is quite extensive.
Asunto(s)
Antioxidantes/farmacología , Isotiocianatos/farmacología , Mitocondrias/fisiología , Animales , Apoptosis , Humanos , Mitocondrias/efectos de los fármacos , Recambio Mitocondrial/efectos de los fármacos , Neoplasias/metabolismo , Estrés Oxidativo , SulfóxidosRESUMEN
Iron accumulation and oxidative stress are hallmarks of retinas from patients with age-related macular degeneration (AMD). We have previously demonstrated that iron-overloaded retinas are a good in vitro model for the study of retinal degeneration during iron-induced oxidative stress. In this model we have previously characterized the role of cytosolic phospholipase A2 (cPLA2) and calcium-independent isoform (iPLA2). The aim of the present study was to analyze the implications of Group V secretory PLA2 (sPLA2), another member of PLA2 family, in cyclooxygenase (COX)-2 and nuclear factor kappa B (NF-κB) regulation. We found that sPLA2 is localized in cytosolic fraction in an iron concentration-dependent manner. By immunoprecipitation (IP) assays we also demonstrated an increased association between Group V sPLA2 and COX-2 in retinas exposed to iron overload. However, COX-2 activity in IP assays was observed to decrease in spite of the increased protein levels observed. p65 (RelA) NF-κB levels were increased in nuclear fractions from retinas exposed to iron. In the presence of ATK (cPLA2 inhibitor) and YM 26734 (sPLA2 inhibitor), the nuclear localization of both p65 and p50 NF-κB subunits was restored to control levels in retinas exposed to iron-induced oxidative stress. Membrane repair mechanisms were also analyzed by studying the participation of acyltransferases in phospholipid remodeling during retinal oxidation stress. Acidic phospholipids, such as phosphatidylinositol (PI) and phosphatidylserine (PS), were observed to show an inhibited acylation profile in retinas exposed to iron while phosphatidylethanolamine (PE) showed the opposite. The use of PLA2 inhibitors demonstrated that PS is actively deacylated during iron-induced oxidative stress. Results from the present study suggest that Group V sPLA2 has multiple intracellular targets during iron-induced retinal degeneration and that the specific role of sPLA2 could be related to inflammatory responses by its participation in NF-κB and COX-2 regulation.