Alexandre Costa - Academia.edu (original) (raw)
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Papers by Alexandre Costa
Febs Letters, 1998
A variety of plant tissues contain an uncoupling mitochondrial protein (PUMP), recently described... more A variety of plant tissues contain an uncoupling mitochondrial protein (PUMP), recently described and characterized by our group. In this study we show that the inhibition of PUMP activity in potato tuber mitochondria significantly increases mitochondrial H P O P generation, while PUMP substrates, such as linoleic acid, reduce mitochondrial H P O P generation. This H P O P generation occurred mainly by the dismutation of superoxide radicals formed through monoelectronic reduction of O P by semiquinone forms of coenzyme Q. The results presented suggest that protection against mitochondrial oxidative stress may be a physiological role of PUMP.
Biochimica Et Biophysica Acta-bioenergetics, 1998
We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optim... more We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optimum efficiency and tune the degree of coupling of oxidative phosphorylation. Uncoupling results from fatty acid cycling, enabled by several phylogenetically specialized proteins and, to a lesser extent, by other mitochondrial carriers. It is suggested that the regulated uncoupling in mammalian mitochondria is provided by uncoupling proteins UCP-1, UCP-2 and UCP-3, whereas in plant mitochondria by PUMP and StUCP, all belonging to the gene family of mitochondrial carriers. UCP-1, and hypothetically UCP-3, serve mostly to provide nonshivering thermogenesis in brown adipose tissue and skeletal muscle, respectively. Fatty acid cycling was documented for UCP-1, PUMP and ADP/ATP carrier, and is predicted also for UCP-2 and UCP-3. UCP-1 mediates a purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H + uniport and uncoupling. UCP-2 is probably involved in the regulation of body weight and energy balance, in fever, and defense against generation of reactive oxygen species. PUMP has been discovered in potato tubers and immunologically detected in fruits and corn, whereas StUCP has been cloned and sequenced from a potato gene library. PUMP is supposed to act in the termination of synthetic processes in mature fruits and during the climacteric respiratory rise.
Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathw... more Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathway in which G i -coupled surface receptors activate a cascade including phosphatidylinositol 3-kinase, endothelial nitric oxide synthase, guanylyl cyclase, and protein kinase G (PKG). Activated PKG opens mitochondrial K ATP channels (mitoK ATP ) which increase production of reactive oxygen species. Steps between PKG and mitoK ATP opening are unknown. We describe effects of adding purified PKG and cGMP on K ϩ transport in isolated mitochondria. Light scattering and respiration measurements indicate PKG induces opening of mitoK ATP similar to K ATP channel openers like diazoxide and cromakalim in heart, liver, and brain mitochondria. This effect was blocked by mitoK ATP inhibitors 5-hydroxydecanoate, tetraphenylphosphonium, and glibenclamide, PKG-selective inhibitor KT5823, and protein kinase C (PKC) inhibitors chelerythrine, Ro318220, and PKC-⑀ peptide antagonist ⑀V 1-2 . MitoK ATP are opened by the PKC activator 12-phorbol 13-myristate acetate. We conclude PKG is the terminal cytosolic component of the trigger pathway; it transmits the cardioprotective signal from cytosol to inner mitochondrial membrane by a pathway that includes PKC-⑀. (Circ Res. 2005;97:329-336.)
Biochimica Et Biophysica Acta-bioenergetics, 2003
Coronary artery disease and its sequelae-ischemia, myocardial infarction, and heart failure-are l... more Coronary artery disease and its sequelae-ischemia, myocardial infarction, and heart failure-are leading causes of morbidity and mortality in man. Considerable effort has been devoted toward improving functional recovery and reducing the extent of infarction after ischemic episodes. As a step in this direction, it was found that the heart was significantly protected against ischemia -reperfusion injury if it was first preconditioned by brief ischemia or by administering a potassium channel opener. Both of these preconditioning strategies were found to require opening of a K ATP channel, and in 1997 we showed that this pivotal role was mediated by the mitochondrial ATP-sensitive K + channel (mitoK ATP ). This paper will review the evidence showing that opening mitoK ATP is cardioprotective against ischemiareperfusion injury and, moreover, that mitoK ATP plays this role during all three phases of the natural history of ischemia -reperfusion injury preconditioning, ischemia, and reperfusion. We discuss two distinct mechanisms by which mitoK ATP opening protects the heart-increased mitochondrial production of reactive oxygen species (ROS) during the preconditioning phase and regulation of intermembrane space (IMS) volume during the ischemic and reperfusion phases. It is likely that cardioprotection by ischemic preconditioning (IPC) and K ATP channel openers (KCOs) arises from utilization of normal physiological processes. Accordingly, we summarize the results of new studies that focus on the role of mitoK ATP in normal cardiomyocyte physiology. Here, we observe the same two mechanisms at work. In low-energy states, mitoK ATP opening triggers increased mitochondrial ROS production, thereby amplifying a cell signaling pathway leading to gene transcription and cell growth. In high-energy states, mitoK ATP opening prevents the matrix contraction that would otherwise occur during high rates of electron transport. MitoK ATP -mediated volume regulation, in turn, prevents disruption of the structure -function of the IMS and facilitates efficient energy transfers between mitochondria and myofibrillar ATPases. D
American Journal of Physiology-heart and Circulatory Physiology, 2005
Febs Letters, 1998
A variety of plant tissues contain an uncoupling mitochondrial protein (PUMP), recently described... more A variety of plant tissues contain an uncoupling mitochondrial protein (PUMP), recently described and characterized by our group. In this study we show that the inhibition of PUMP activity in potato tuber mitochondria significantly increases mitochondrial H P O P generation, while PUMP substrates, such as linoleic acid, reduce mitochondrial H P O P generation. This H P O P generation occurred mainly by the dismutation of superoxide radicals formed through monoelectronic reduction of O P by semiquinone forms of coenzyme Q. The results presented suggest that protection against mitochondrial oxidative stress may be a physiological role of PUMP.
Biochimica Et Biophysica Acta-bioenergetics, 1998
We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optim... more We hypothesize that fatty acid-induced uncoupling serves in bioenergetic systems to set the optimum efficiency and tune the degree of coupling of oxidative phosphorylation. Uncoupling results from fatty acid cycling, enabled by several phylogenetically specialized proteins and, to a lesser extent, by other mitochondrial carriers. It is suggested that the regulated uncoupling in mammalian mitochondria is provided by uncoupling proteins UCP-1, UCP-2 and UCP-3, whereas in plant mitochondria by PUMP and StUCP, all belonging to the gene family of mitochondrial carriers. UCP-1, and hypothetically UCP-3, serve mostly to provide nonshivering thermogenesis in brown adipose tissue and skeletal muscle, respectively. Fatty acid cycling was documented for UCP-1, PUMP and ADP/ATP carrier, and is predicted also for UCP-2 and UCP-3. UCP-1 mediates a purine nucleotide-sensitive uniport of monovalent unipolar anions, including anionic fatty acids. The return of protonated fatty acid leads to H + uniport and uncoupling. UCP-2 is probably involved in the regulation of body weight and energy balance, in fever, and defense against generation of reactive oxygen species. PUMP has been discovered in potato tubers and immunologically detected in fruits and corn, whereas StUCP has been cloned and sequenced from a potato gene library. PUMP is supposed to act in the termination of synthetic processes in mature fruits and during the climacteric respiratory rise.
Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathw... more Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathway in which G i -coupled surface receptors activate a cascade including phosphatidylinositol 3-kinase, endothelial nitric oxide synthase, guanylyl cyclase, and protein kinase G (PKG). Activated PKG opens mitochondrial K ATP channels (mitoK ATP ) which increase production of reactive oxygen species. Steps between PKG and mitoK ATP opening are unknown. We describe effects of adding purified PKG and cGMP on K ϩ transport in isolated mitochondria. Light scattering and respiration measurements indicate PKG induces opening of mitoK ATP similar to K ATP channel openers like diazoxide and cromakalim in heart, liver, and brain mitochondria. This effect was blocked by mitoK ATP inhibitors 5-hydroxydecanoate, tetraphenylphosphonium, and glibenclamide, PKG-selective inhibitor KT5823, and protein kinase C (PKC) inhibitors chelerythrine, Ro318220, and PKC-⑀ peptide antagonist ⑀V 1-2 . MitoK ATP are opened by the PKC activator 12-phorbol 13-myristate acetate. We conclude PKG is the terminal cytosolic component of the trigger pathway; it transmits the cardioprotective signal from cytosol to inner mitochondrial membrane by a pathway that includes PKC-⑀. (Circ Res. 2005;97:329-336.)
Biochimica Et Biophysica Acta-bioenergetics, 2003
Coronary artery disease and its sequelae-ischemia, myocardial infarction, and heart failure-are l... more Coronary artery disease and its sequelae-ischemia, myocardial infarction, and heart failure-are leading causes of morbidity and mortality in man. Considerable effort has been devoted toward improving functional recovery and reducing the extent of infarction after ischemic episodes. As a step in this direction, it was found that the heart was significantly protected against ischemia -reperfusion injury if it was first preconditioned by brief ischemia or by administering a potassium channel opener. Both of these preconditioning strategies were found to require opening of a K ATP channel, and in 1997 we showed that this pivotal role was mediated by the mitochondrial ATP-sensitive K + channel (mitoK ATP ). This paper will review the evidence showing that opening mitoK ATP is cardioprotective against ischemiareperfusion injury and, moreover, that mitoK ATP plays this role during all three phases of the natural history of ischemia -reperfusion injury preconditioning, ischemia, and reperfusion. We discuss two distinct mechanisms by which mitoK ATP opening protects the heart-increased mitochondrial production of reactive oxygen species (ROS) during the preconditioning phase and regulation of intermembrane space (IMS) volume during the ischemic and reperfusion phases. It is likely that cardioprotection by ischemic preconditioning (IPC) and K ATP channel openers (KCOs) arises from utilization of normal physiological processes. Accordingly, we summarize the results of new studies that focus on the role of mitoK ATP in normal cardiomyocyte physiology. Here, we observe the same two mechanisms at work. In low-energy states, mitoK ATP opening triggers increased mitochondrial ROS production, thereby amplifying a cell signaling pathway leading to gene transcription and cell growth. In high-energy states, mitoK ATP opening prevents the matrix contraction that would otherwise occur during high rates of electron transport. MitoK ATP -mediated volume regulation, in turn, prevents disruption of the structure -function of the IMS and facilitates efficient energy transfers between mitochondria and myofibrillar ATPases. D
American Journal of Physiology-heart and Circulatory Physiology, 2005