ORIGINAL PAPER The Interplay Between Apoptosis, Mitophagy and Mitochondrial Biogenesis Induced by Resveratrol Can Determine Activated Hepatic Stellate Cells Death or Survival Leo A. Meira Martins • Moema Queiroz Vieira • Mariana Ilha • Mariana de Vasconcelos • Henrique B. Biehl • Daniela B. Lima • Vanessa Schein • Florencia Barbe ´-Tuana • Radovan Borojevic • Fa ´tima Costa Rodrigues Guma Ó Springer Science+Business Media New York 2014 Abstract Resveratrol has been the focus of numerous studies reporting opposite effects that depend on its con- centration. The GRX is an activated hepatic stellate cells model used to study liver fibrosis development and reso- lution. We recently showed that GRX treatment with RSV (0.1–50 lM) for 24 h triggered dose-dependent pro-oxi- dant effects, resulting in cytotoxicity and cell damage only at the highest concentration. Here, we evaluated whether the pro-oxidant effect of resveratrol treatment is accom- panied by alterations on the GRX mitochondrial metabo- lism, and whether the concomitantly autophagy/mitophagy induction can influence on cell death or survival. We demonstrated that all concentrations of resveratrol pro- moted an increase of GRX cell death signals, altering the mitochondrial dynamics and function. Cells treated with all resveratrol concentrations presented higher autophagy/ mitophagy features, but only treatments with 1 and 10 lM of resveratrol-induced mitochondrial biogenesis. Since cell damage was higher and there was no mitochondrial bio- genesis in GRX treated with 50 lM of resveratrol, we suggest that these cells failed to remove and replace all damaged mitochondria. In conclusion, the cytotoxic effect of resveratrol that effectively promotes cell death could be related to the interrelation between the concomitant induction of apoptosis, autophagy/mitophagy and mito- chondrial biogenesis in GRX. Keywords Autophagy Á Cell death Á Cytotoxicity Á GRX Á Hepatic stellate cells Á Liver fibrosis Á Mitophagy Á Resveratrol Introduction Resveratrol (3,5,4 0 -trihydroxystilbene; RSV) is a flavonoid characterized as a phytoalexin, an anti-infectious com- pound produced by several plant species, including peanuts and grapes, in response to pathogenic infection and envi- ronmental stresses [1]. This polyphenolic compound has been associated to beneficial effects in normal cells through its chemoprevention activity [2,3] among which are the induction of neuroprotection under adverse conditions such as oxygen or glucose deprivation [4], the cardioprotection by preventing coronary heart diseases or damage to cardiac tissue due to ischaemia [3, 5], and the contribution to an anti-diabetic effect by protecting pancreatic b cells [6]. These RSV effects are usually associated to its anti- inflammatory, anti-apoptotic and antioxidant activities [3]. Nonetheless, RSV can also exert cytotoxicity through modulation of several pathways and induction of different mechanisms of cell death and growth inhibition, which Electronic supplementary material The online version of this article (doi:10.1007/s12013-014-0245-5) contains supplementary material, which is available to authorized users. L. A. Meira Martins (&) Á M. Q. Vieira Á M. Ilha Á M. de Vasconcelos Á D. B. Lima Á V. Schein Á F. Barbe ´-Tuana Á F. C. R. Guma Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul (UFRGS), rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS CEP 90035-003, Brazil e-mail: leo.meira@ufrgs.br M. Q. Vieira Á H. B. Biehl Electron Microscopy Center, Federal University of Rio Grande do Sul (UFRGS), avenida Bento Gonc ¸alves, 9500, Porto Alegre, RS CEP 91509-900, Brazil R. Borojevic Department of Histology and Embriology, ICB, PABCAM, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil 123 Cell Biochem Biophys DOI 10.1007/s12013-014-0245-5