COMUNICACIÓN RETÍCULO SARCOPLASMÁTICO-MITOCONDRIA EN LA APOPTOSIS DEL CORAZON PREDIABETICO- ROL DE CaMKII

PALOMEQUE J; BLANCO P; A. MATTIAZZI; SOMMESE L; PORTIANSKY E; FEDERICO M

Les Diablerets

Seminario; Gordon Research Seminars; 2017

Gordon Reseach Conferences

Communication between sarcoplasmic reticulum (SR) and mitochondrion through calcium (Ca2+) results pivotal in either physiological (fight or flight response) or pathological (apoptosis) situations. Furthermore, the stages of insulin-resistance or impaired glucose tolerance occur whit Ca2+mishandling, increased reactive oxygen species (ROS), and activation of CaMKII, events associated whit cardiac apoptosis. For this reason, we proposed studying the apoptotic pathways in the heart with impaired glucose tolerance, and the relationship between the sarcoplasmic reticulum (SR) and mitochondria in this scenario.To evaluate this aim, we use wild type (WT) mice or mutant mice. WT mice or SR-AIP mice (express an inhibitor of CaMKII target SR membrane), S2814A mice (express the CaMKII RyR2 phosphor-site mutated to alanine), and AC3I mice (express a peptide inhibitor of CaMKII at the whole heart level), were fed whit a control diet (CD) or by a fructose-rich diet (FRD), supplementing water whit 10% fructose.FRD mice showed increased cardiac apoptosis (Bax/Bcl2 ratio [273.6±39.7%] and increased positive TUNEL nuclei) and ROS (88.2±13.2%), respect to CD mice. Furthermore, FRD myocytes presented significant increase in spontaneous Ca2+ release events (SCaRE) and mitochondria from FRD mice showed significant swelling and depolarization with respect to CD. When we co-treatment whit TEMPOL, a chelating agent of ROS, WT FRD were prevented for the increase in ROS, SCaRE, and apoptosis. Moreover, in SR-AIP mice both CD and FRD, we did not find neither SCaRE nor apoptosis in spite of increased ROS. In line, mitochondrial swelling and depolarization was prevented in S2814A FRD mice. Through electron microscopy we found that the distance between SR and mitochondria was markedly decreased in FRD mice respect to CD (20.3±0.6 vs 9.4±0.3nm, CD vs DRF respectively), and this result was prevented in AC3I mice.The results would indicate that the proximity between mitochondria and RS would be essential in promoting Ca+2 trafficking between the organelles. The more proximity, the worse outcome to the heart with the impaired glucose tolerance. In fact, there is a causal link between CaMKII activation by ROS, SR Ca2+ leak produced by CaMKII-dependent phosphorylation of RyR2 and mitochondria damage.