MITOCHONDRIAL PERMEABILITY TRANSITION PORE AND CALCIUM HANDLING IN DIABETIC HEARTS

CAROLINA JAQUENOD DE GIUSTI; FERNANDA CARRIZO VELASQUEZ

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI SAFIS 2018; 2018

SAIC, SAI,SAFIS

Mitochondrial dysfunction underlies the causes of many cardiac diseases. The mitochondrial death pathway features the sequential loss of mitochondrial membrane potential (ΔΨm), accompanied by irreversible opening of the mitochondrial permeability transition pore (MPTP), release of reactive oxygen species and toxic proteins into the cytoplasm, and activation of caspases. The NHE1 Na+/H+ exchanger has been associated with cardiac disorders and was recently located in cardiomyocytes mitochondria. The specific NHE1 inhibitor, cariporide (HOE642), is cardioprotective through its effects on mitochondria and its beneficial effect in hearts subjected to I/R has been associated with attenuation of MPTP opening and reduction of apoptosis, reducing mitochondrial dysfunction. In addition, inhibition of mitochondrial NHE1 during ischemia delays the progression of ischemic injury by decreasing cell death. Recently, abnormal mitochondrial Ca2+ handling was demonstrated in the hearts fromspontaneously hypertensive rats (SHR). SHR heart mitochondria displayed reduced Ca2+ retention capacity and lower ΔΨm compared to control hearts.We aim to study the role of the MPTP in the cardiac dysfunction of diabetic hearts that leads to diabetic cardiomyopathy. Our results showed decreased swelling after Ca2+ addition in the mitochondria from the obese diabetic heart (ODH) that could be due to reduced Ca2+ uptake activity. In order to define this mechanism we studied the calcium retention capacity (CRC) exposing mitochondria to small Ca2+ pulses to test CRC before MPTP opening. Mitochondria from obese mice showed reduced CRC confirming the increased mitochondrial Ca2+ load. Finally, we studied the role of the NHE1 in the increased Ca2+ load from ODH mitochondria. Inhibiting NHE1 with HOE642 resulted on increased CRC in the ODH mitochondria, confirming the deleterious role of NHE1 on the mitochondrial Ca2+overload. Our results show that increased mitochondrial NHE1 expression and NHE1-prompt Ca2+ overload could be important factors for the development of diabetic cardiomyopathy.