Valenti 2015 Abstract MiPschool London 2015
|Different modulation of mitochondrial function by epigallocatechin-3 gallate in human disease: a matter of life and death.|
Event: MiPschool London 2015
Mitochondria play a crucial role in cell life and death, thus it is unsurprising that mitochondrial damage contributes to a wide range of pathologies including neurodegenerative diseases and cancer. We have recently show a deficit in ATP production via oxidative phosphorylation (OXPHOS) and overproduction of reactive oxygen species (ROS) by mitochondria in Down syndrome (DS), a genetic neurodegenerative disorder caused by trisomy of chromosome 21 [1,2]; conversely, we described a correlation between enhanced OXPHOS and tumor proliferation in malignant epithelial pleural mesothelioma (MMe), a rare but highly aggressive tumor . Consequently mitochondria could be promising targets for the development of efficient anti-cancer therapies and to correct clinical phenotypes linked to increased oxidative stress and energy deficit.
We checked the ability of epigallocatechin-3-gallate (EGCG) - a natural polyphenol component of green tea, known to selectively target mitochondria and to have beneficial effects in a broad range of diseases - to counteract the mitochondrial energy deficit found in DS cells, as well as to impair mitochondrial energy production and cell viability in human MMe cells. The rate of mitochondrial ATP production by OXPHOS was determined photometrically as in . Isolation of mitochondrial membrane-enriched fractions and measurement of mitochondrial respiratory chain complexes activity was performed essentially as in . Intracellular ROS were measured by fluorimetric and confocal analysis as in . Measurements of cellular cAMP levels, PKA activity and serine phosphorylation were carried out as in . We found that under pathological conditions in which an energy deficit is present, as in the case of Down syndrome, EGCG (10-20 µM) exerts a cytoprotective effect acting as a promoting effector of OXPHOS and mitochondrial biogenesis in DS cells through modulation of the cAMP/PKA- and sirtuin-dependent pathways . Conversely, in MMe cancer cells EGCG, used at higher concentrations (100 µM), becomes cytotoxic and exerts an inhibitory action on cell proliferation via a negative modulation of mitochondrial energy metabolism .
The EGCG-dependent modulation of mitochondrial energy metabolism, could give important inputs for the development of novel pharmacological strategies selectively targeted to specific pathologies.
Labels: Pathology: Cancer Stress:Oxidative stress;RONS
Tissue;cell: Endothelial;epithelial;mesothelial cell
Coupling state: OXPHOS
Inst Biomembr Bioenerg - Nat Council Research, Bari, Italy. - [email protected]
References and support
Supported in part by Fondation Jerome Lejeune (VACCA/1093-VR2012B) and CNR Project "FaReBio di Qualità"
- Valenti D, Tullo A, Caratozzolo MF, Merafina RS, Scartezzini P, Marra E, Vacca RA (2010) Impairment of F1F0-ATPase, adenine nucleotide translocator and adenylate kinase causes mitochondrial energy deficit in human skin fibroblasts with chromosome 21 trisomy. Biochem J 431:299-310.
- Valenti D, Manente GA, Moro L, Marra E, Vacca RA (2011) Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway. Biochem J 435: 679-88.
- Valenti D, de Bari L, Manente GA, Rossi L, Mutti L, Moro L, Vacca RA (2013) Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells. Biochim Biophys Acta 1832:542-52.
- Valenti D, De Rasmo D, Signorile A, Rossi L, de Bari L, Scala I, Granese B, Papa S, Vacca RA (2013) Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome. Biochim Biophys Acta 1832:2085-96.