Nejvíce citovaný článek - PubMed ID 24182344
Biguanides inhibit complex I, II and IV of rat liver mitochondria and modify their functional properties
Life manifests as growth, movement or heat production that occurs thanks to the energy accepted from the outside environment. The basis of energy transduction attracted the Czech researchers since the beginning of the 20th century. It further accelerated after World War II, when the new Institute of Physiology was established in 1954. When it was found that energy is stored in the form of adenosine triphosphate (ATP) that can be used by numerous reactions as energy source and is produced in the process called oxidative phosphorylation localized in mitochondria, the investigation focused on this cellular organelle. Although the Czech scientists had to overcome various obstacles including Communist party leadership, driven by curiosity, boldness, and enthusiasm, they characterized broad spectrum of mitochondrial properties in different tissues in (patho)physiological conditions in collaboration with many world-known laboratories. The current review summarizes the contribution of the Czech scientists to the bioenergetic and mitochondrial research in the global context. Keywords: Mitochondria, Bioenergetics, Chemiosmotic coupling.
- MeSH
- biomedicínský výzkum dějiny trendy MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- energetický metabolismus * MeSH
- lidé MeSH
- mitochondrie * metabolismus MeSH
- zvířata MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with a wide range of functions. Although the MPTP has been studied for more than 50 years, its molecular structure remains unclear. Short-term (reversible) opening of the MPTP protects cells from oxidative damage and enables the efflux of Ca2+ ions from the mitochondrial matrix and cell signaling. However, long-term (irreversible) opening induces processes leading to cell death. Ca2+ ions, reactive oxygen species, and changes in mitochondrial membrane potential regulate pore opening. The sensitivity of the pore to Ca2+ ions changes as an organism ages, and MPTP opening plays a key role in the pathogenesis of many diseases. Most studies of the MPTP have focused on elucidating its molecular structure. However, understanding the mechanisms that will inhibit the MPTP may improve the treatment of diseases associated with its opening. To evaluate the functional state of the MPTP and its inhibitors, it is therefore necessary to use appropriate methods that provide reproducible results across laboratories. This review summarizes our current knowledge of the function and regulation of the MPTP. The latter part of the review introduces two optimized methods for evaluating the functional state of the pore under standardized conditions.
- Klíčová slova
- calcium retention capacity, calcium signaling, calcium-induced swelling, mitochondria, mitochondrial permeability transition, mitochondrial permeability transition pore,
- MeSH
- buněčná smrt MeSH
- mitochondrie metabolismus MeSH
- přechodový pór mitochondriální permeability * metabolismus MeSH
- transportní proteiny mitochondriální membrány * metabolismus MeSH
- vápník metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- přechodový pór mitochondriální permeability * MeSH
- transportní proteiny mitochondriální membrány * MeSH
- vápník MeSH
Metformin is widely prescribed as a first-choice antihyperglycemic drug for treatment of type 2 diabetes mellitus, and recent epidemiological studies showed its utility also in cancer therapy. Although it is in use since the 1970s, its molecular target, either for antihyperglycemic or antineoplastic action, remains elusive. However, the body of the research on metformin effect oscillates around mitochondrial metabolism, including the function of oxidative phosphorylation (OXPHOS) apparatus. In this study, we focused on direct inhibitory mechanism of biguanides (metformin and phenformin) on OXPHOS complexes and its functional impact, using the model of isolated brown adipose tissue mitochondria. We demonstrate that biguanides nonspecifically target the activities of all respiratory chain dehydrogenases (mitochondrial NADH, succinate, and glycerophosphate dehydrogenases), but only at very high concentrations (10-2-10-1 M) that highly exceed cellular concentrations observed during the treatment. In addition, these concentrations of biguanides also trigger burst of reactive oxygen species production which, in combination with pleiotropic OXPHOS inhibition, can be toxic for the organism. We conclude that the beneficial effect of biguanides should probably be associated with subtler mechanism, different from the generalized inhibition of the respiratory chain.
- MeSH
- biguanidy farmakologie MeSH
- fenformin farmakologie MeSH
- glycerolfosfátdehydrogenasa metabolismus MeSH
- hnědá tuková tkáň cytologie MeSH
- hypoglykemika farmakologie MeSH
- krysa rodu Rattus MeSH
- kyselina jantarová metabolismus MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- metformin farmakologie MeSH
- mitochondrie účinky léků metabolismus MeSH
- oxidace-redukce účinky léků MeSH
- peroxid vodíku farmakologie MeSH
- potkani Wistar MeSH
- reaktivní formy kyslíku metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biguanidy MeSH
- fenformin MeSH
- glycerolfosfátdehydrogenasa MeSH
- hypoglykemika MeSH
- kyselina jantarová MeSH
- metformin MeSH
- peroxid vodíku MeSH
- reaktivní formy kyslíku MeSH
Epigallocatechin gallate (EGCG) is a green tea antioxidant with adverse effects on rat liver mitochondria and hepatocytes at high doses. Here, we assessed whether low doses of EGCG would protect these systems from damage induced by tert-butyl hydroperoxide (tBHP). Rat liver mitochondria or permeabilized rat hepatocytes were pretreated with EGCG and then exposed to tBHP. Oxygen consumption, mitochondrial membrane potential (MMP), and mitochondrial retention capacity for calcium were measured. First, 50 μM EGCG or 0.25 mM tBHP alone increased State 4 Complex I-driven respiration, thus demonstrating uncoupling effects; tBHP also inhibited State 3 ADP-stimulated respiration. Then, the coexposure to 0.25 mM tBHP and 50 μM EGCG induced a trend of further decline in the respiratory control ratio beyond that observed upon tBHP exposure alone. EGCG had no effect on MMP and no effect, in concentrations up to 50 μM, on mitochondrial calcium retention capacity. tBHP led to a decline in both MMP and mitochondrial retention capacity for calcium; these effects were not changed by pretreatment with EGCG. In addition, EGCG dose-dependently enhanced hydrogen peroxide formation in a cell- and mitochondria-free medium. Conclusion. Moderate nontoxic doses of EGCG were not able to protect rat liver mitochondria and hepatocytes from tBHP-induced mitochondrial dysfunction.
- MeSH
- hepatocyty cytologie účinky léků metabolismus MeSH
- jaterní mitochondrie účinky léků metabolismus MeSH
- katechin analogy a deriváty farmakologie MeSH
- krysa rodu Rattus MeSH
- kultivované buňky MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- peroxid vodíku metabolismus MeSH
- potkani Wistar MeSH
- spotřeba kyslíku účinky léků MeSH
- terc-butylhydroperoxid toxicita MeSH
- vápník metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- epigallocatechin gallate MeSH Prohlížeč
- katechin MeSH
- peroxid vodíku MeSH
- terc-butylhydroperoxid MeSH
- vápník MeSH