RESUMEN
Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.
Asunto(s)
Mitocondrias Cardíacas , Sodio , Animales , Ratas , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de los fármacos , Sodio/metabolismo , Masculino , Miocardio/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Adenosina Trifosfato/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Ratas Sprague-Dawley , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Ubiquinona/metabolismo , Ubiquinona/análogos & derivados , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Oxidación-Reducción , Ácido Succínico/metabolismoRESUMEN
The terminal enzyme of the mitochondrial respiratory chain, cytochrome oxidase, transfers electrons to molecular oxygen, generating water. Within the inner mitochondrial membrane, cytochrome oxidase assembles into supercomplexes, together with other respiratory chain complexes, forming so-called respirasomes. Little is known about how these higher oligomeric structures are attained. Here we report on Rcf1 and Rcf2 as cytochrome oxidase subunits in S. cerevisiae. While Rcf2 is specific to yeast, Rcf1 is a conserved subunit with two human orthologs, RCF1a and RCF1b. Rcf1 is required for growth in hypoxia and complex assembly of subunits Cox13 and Rcf2, as well as for the oligomerization of a subclass of cytochrome oxidase complexes into respirasomes. Our analyses reveal that the cytochrome oxidase of mitochondria displays intrinsic heterogeneity with regard to its subunit composition and that distinct forms of respirasomes can be formed by complex variants.