Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

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.

Keywords: TCA cycle metabolites; kidney diseases; mitochondria.

Figure 1

The tricarboxylic acid (TCA) cycle. The TCA cycle is an amphibolic route with anabolic and catabolic reactions. Anaplerotic reactions include the net input of amino acids in the cycle and the generation of oxaloacetate from pyruvate through pyruvate carboxylase. Among the main products of the TCA cycle are guanosine triphosphate (GTP), dinucleotide nicotinamide molecules (NADH), and dinucleotide adenine flavine molecule (FADH₂); the latter are electron donors to feed the electron transport system (ETS). PDC: pyruvate dehydrogenase complex, ACSS: acetyl CoA synthetase, ACLY: ATP-citrate lyase, Irg1: the immune responsive gene 1 protein, CS: citrate synthase, IDH: isocitrate dehydrogenase, AKG DH: alpha-ketoglutarate dehydrogenase, SS: succinyl CoA synthetase, SDH: succinate dehydrogenase, FH: fumarate hydratase, MDH: malate dehydrogenase, NAD⁺: nicotinamide adenine dinucleotide (oxidized form), FAD: flavine adenine dinucleotide (oxidized form), GDP: guanosine diphosphate. Created with Biorender.com.

Figure 2

Involvement of TCA cycle metabolites in kidney functions. The metabolites of the TCA cycle and acetyl-CoA participate as signal molecules to promote several critical cellular functions such as epigenetic modifications, redox regulation, hypoxic response, and immunity. Nrf-2: nuclear factor erythroid 2–related factor 2, ARE: antioxidant response element, maf: musculoaponeurotic fibrosarcoma protein, CAT: catalase, SOD: superoxide dismutase, GPx: glutathione peroxidase, 2OGDD: named 2-oxoglutarate dependent dioxygenases, HIF: hypoxia inducible factor, EMT: epithelial-mesenchymal transition, SDH: succinate dehydrogenase. Created with Biorender.com.