Abstract
Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.
Highlights
Mitochondria are organelles that fulfill a wide variety of functions in the cell
Acetyl-CoA is not inside the tricarboxylic acid (TCA) cycle, it is a highly relevant molecule as it is required in the first step, which reacts with OAA to give rise to citrate; interestingly, citrate can be shuttled out from the mitochondrial matrix to the cytosol, where it can be re-converted to acetyl-CoA and OAA
Since hypoxiainducible factor (HIF) is necessary for erythropoiesis induction, PHD inhibitor (PHI) roxadustat and GSK1278863 has been proposed for anemia treatment in chronic kidney disease (CKD), demonstrating the increase in erythropoietin and hematocrit levels in animal models [103,104] and even in patients [105]; in CKD and acute kidney injury (AKI), there is an increase in Prolyl hydroxylases (PHD) activity, and their inhibition ameliorates damage associated with kidney dysfunction
Summary
Mitochondria are organelles that fulfill a wide variety of functions in the cell. In addition to being a bioenergetics node, they serve as signal organelles that communicate to the rest of the cell through different mechanisms. The tricarboxylic acid (TCA) cycle, named the citric acid cycle and Krebs cycle ( this last name can be dissected in the three different cycles: the urea, the glyoxylate, and TCA cycles) was described by Hans Krebs and his colleagues [7] It is known for producing electron donors, the reduced form of nicotinamide adenine dinucleotide (NADH), and the reduced form of flavin adenine dinucleotide (FADH2 ) to feed the electrons transport system (ETS). Their intermediates can serve as signal molecules to drive several cell functions. Mitochondrial alterations, such as dynamics (fusion/fission), homeostasis (biogenesis/mitophagy), and bioenergetics, impact on kidney function. Other metabolic functions of the mitochondrial, such as the TCA cycle, could be involved in kidney diseases
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