SR-MITOCHONDRIA COMMUNICATION PROMOTES MITOCHONDRIAL DAMAGE AND TISSUE DISARRANGEMENT IN PREDIABETIC HEARTS

TAMARA VICO; SILVIA ALVAREZ; MARILEN FEDERICO; ENRIQUE PORTIANSKY; MARÍA C. VILLA-ABRILLE; MAITE R. ZAVALA; SOFÍA LÓPEZ; JULIETA PALOMEQUE

Mar del Plata

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

SR-mitochondria communication plays an essential role in pathophysiological heart conditions. Prediabetic hearts present Ca2+ mishandling by CaMKII (Ca2+-Calmodulin kinase II) hyperactivity. Mitochondrial Ca2+ overload can open 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, induce a decreased mitochondrial Ca2+ retention capacity (CRC) inducing mitochondrial damage. We measured spontaneous Ca2+ release events (SCaRE), RyR2 activity by [3H]Ryanodine 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 (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, tether 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 increased with a decreased respiratory control ratio 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 without changes in Opa1 in WT FRD vs CD. We conclude that CaMKII hyperactivity induces 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, where myocardial CaMKII is genetically inhibited.