SR- leak, mitochondria injury and SR-mitochondria miscommunication culminate in apoptosis in prediabetic hearts

FEDERICO MARILEN,; LÓPEZ SOFÍA, ; ZAVALA MAITE, ; VICO TAMARA,; PORTIANSKY ENRIQUE,; ALVAREZ SILVIA, ; VILLA ABRILLE CELESTE, ; MATTIAZZI ALICIA, ; PALOMEQUE JULIETA

Rosario

Congreso; Reunión SAFIS 2019; 2019

SR- leak, mitochondria injury and SR-mitochondria miscommunication culminate in apoptosis in prediabetic heartsFederico Marilen(1), López Sofía(1), Zavala Maite(1), Vico Tamara(3), Portiansky Enrique(4), Alvarez Silvia(3), Villa Abrille Celeste(1), Mattiazzi Alicia(1), Palomeque Julieta(1,5)Prediabetic hearts present Ca2+ mishandling, Ca2+-calmodulin kinase II (CaMKII) hyperactivity, mitochondria injury, ultrastructure disarrangements and apoptosis. The SR-mitochondria interplay is pivotal in patho-physiological situations (included metabolic diseases) and mitochondria structure and metabolisms is essential to fate of cells. We hypothesize that in prediabetic hearts, SR-Ca2+ leak is due to increased ryanodine receptors 2 (RyR2) activity via CaMKII-dependent pathway, which in turn produces mitochondrial Ca2+ overload, mitochondrial metabolic changes, which play a role in the enhanced SR-mitochondria proximity of prediabetic hearts and ultrastructure alterations.We measured spontaneous Ca2+ release events (SCaRE), 3H-Ryanodine ([3H]Ry) binding assay, mitochondrial Ca2+ retention capacity (CRC), ATP and H2O2 production, and O2 uptake, morphology and fission/fusion proteins expression in a prediabetic model induced by fructose rich diet (FRD) in WT and AC3I mice, which express a CaMKII-inhibitor at heart level. Confocal images showed significantly increased SCaRE in WT FRD vs WT CD myocytes, which were prevented in AC3I mice. [3H]Ry binding assay revealed higher Bmax in WT FRD than WT CD and AC3I FRD. In isolated mitochondria, CRC, ATP production rate and O2 uptake were decreased, while H2O2 production rate was increased. Transmission Electron Microscopy photographs showed decreased mitochondria area and diameter in WT FRD respect to WT CD, whereas Feret diameter and roundness was higher in WT FRD than WT CD. A clear disarrangement in WT-FRD tissue was evident. A decreased pDRP-1 was found and no differences were found in Mfn-2 or OPA-1 in WT FRD. We conclude that CaMKII is involved in the increase of RyR2 activity, SR Ca2+ leak and mitochondria morphology changes of FRD. Moreover, the increased in SR Ca2+ leak and SR-mitochondria proximity would favor the decreased CRC, favoring mitochondrial Ca2+ overload and decrease mitochondrial bioenergetics: increased mitochondrial H2O2 production and decreased O2 consumption and ATP production. Finally, fission process are present without fusion.