IBIMOL   23987
INSTITUTO DE BIOQUIMICA Y MEDICINA MOLECULAR PROFESOR ALBERTO BOVERIS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
SR-Mitochondria communication promotes mitochondrial damage and tissue disarrangement in prediabetic hearts
Autor/es:
VICO, TAMARA ANTONELA; ALVAREZ, SILVIA; FEDERICO, MARILÉN; LÓPEZ, SOFÍA; VILLA ABRILLE, CELESTE; ZAVALA, MAITE; PORTIANSKY, ENRIQUE; PALOMEQUE, JULIETA
Reunión:
Congreso; Reunión Anual de Sociedades de Biociencia; 2020
Resumen:
SR-mitochondria communication plays an essential role in pathophysiological situations in the heart. Prediabetic hearts present Ca2+ mishandling by CaMKII (Ca2+-Calmodulin kinase II) hyperactivity. Mitochondrial Ca2+ overload can open the mitochondrial permeability transition pore (MPTP) and trigger cell death. We hypothesize that SR Ca2+ leak through RyR2 and the decreased distance between organelles in a CaMKII-dependent pathway can reach more easily the mitochondria and produces mitochondrial damage. We measured spontaneous Ca2+ release events (SCaRE), RyR2 activity by 3H-Ryanodine ([3H]Ry) binding assay, mitochondrial CRC, O2 consumption and ATP and H2O2 production, mitochondrial morphology and fission/fusion processes in a prediabetic model induced by fructose-rich diet (FRD) in WT and AC3I mice, which express a CaMKII-inhibitor at heart level. We found significantly increased SCaRE and RyR2 activity in WT FRD vs CD, without changes in AC3I hearts. Increased expression of Mfn2, VDAC and Grp75, linker proteins that could explain the decreased distance between organelles, was found in WT FRD vs CD.In isolated mitochondria, O2 consumption in state 4 was increase with a decreased respiratory control ratio (RCR) and without changes in ATP production. Moreover, H2O2 production rate was increased. Transmission Electron Microscopy photographs showed decreased mitochondria size and number, plus a clear disarrangement in the tissue of WT FRD vs CD. DRP1 was found increased and no differences were found in OPA-1 in WT FRD vs CD. We conclude that CaMKII hyperactivity induces the SR Ca2+ leak by RyR2 hyperactivity, which in turn increases mitochondrial Ca2+ content and decreases CRC due to, at least in part, the nearness between the two organelles. Besides, the ETC is partially uncoupled and H2O2 production increases in agreement with mitochondrial fragmentation and tissue disarrangement. These events are prevented in AC3I mice, which have myocardial CaMKII inhibited.