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Review
. 2022 Feb 19;27(4):1416.
doi: 10.3390/molecules27041416.

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

Maria João Correia  1 , António B Pimpão  1 , Dalila G F Fernandes  2 , Judit Morello  1 , Catarina O Sequeira  1 , Joaquim Calado  3   4 , Alexandra M M Antunes  5 , Manuel S Almeida  1   6 , Patrícia Branco  1   6 , Emília C Monteiro  1 , João B Vicente  2 , Jacinta Serpa  1   7 , Sofia A Pereira  1
Affiliations
Review

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

Maria João Correia et al. Molecules. .

Abstract

In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.

Keywords: H2S; bioenergetics; cysteine transporters; cysteine-related thiolome; ferroptosis; glutathione; hypertension; hypoxia; kidney metabolism; lysosomes.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of the data; in the writing of the manuscript or in the decision to publish the results.

Figures

Figure 1
Figure 1
Cysteine supply and metabolic circuits for the renal epithelial proximal tubular cells. The net intracellular supply of cysteine is a sum of different contributions. After glomerular filtration, there is an increase in the proximal tubule luminal content of CysSSP and also of glutathione (can also be secreted) and cysteine disulfides (CysSSX, mainly cystine). CysSSP undergoes reabsorption by lysosomal-mediated uptake [30,31,32,33] (A). CysSS is reabsorbed by cysteine-related transporters that include the heterodimer b0,+AT-rBAT, encoded respectively by SLC7A9-SLC3A1 [34,35]) (B). PEPT2 (encoded by Slc15a2) apical influx of CysGly [36] also contributes toto cysteine intracellular availability (C). The extracellular thiol pool that nourishes the kidney tubular cell with Cys also has the contribution of the mercapturate pathway (D). The GGT, the first enzyme of the mercapturate pathway, has the highest activity in kidney epithelial tubular cells and hydrolyzes glutathione, contributing with CysGly and cysteine disulfides for the pool. The trans-epithelial transport of cysteine involves is the taken up through the brush border membrane (B) and its exit through the 4F2hc/LAT-2 transporter at the basolateral membrane [37] (E). Once inside the cell, cystine and CysGly are converted in Cys, which may undergo several metabolic circuitries: H2S-producing enzymatic pathways, CDO-mediated oxidative metabolism, GSH synthesis and protein incorporation (F). Intracellular CysSSX may also be N-acetylated by the last mercapturate pathway activity of NAT8 and eliminated in urine (G). CDO: cysteine dioxygenase; CTNS: cystinosin; Cys: cysteine; CysGly: cysteinylglycine; CysSSP: cysteinylated proteins; DP: Dipeptidases; GGT: γ-glutamyl transpeptidase; GSH: glutathione; H2S: hydrogen sulfide; PTCs: proximal tubular cells. Created with Biorender.com; accessed on 22 January 2022.
Figure 2
Figure 2
Organ dependence of the cysteine-related thiolome. Principal Component Analysis (Score plot) with all studied organs; first two components covered 77 and 15% of the variance of the data, respectively. A total of 17 samples of brain tissue, 33 of kidney tissue and 53 of liver tissue were analyzed. PC: Principal Component.
Figure 3
Figure 3
Tissue-specific thiol distribution amongst the organs. Principal Component Analysis with all organs; biplot displaying the plot score and the loadings plot. CysGly: cysteinylglycine; CysGlySSP: cysteinylglycinated proteins; CysSSP: cysteinylated proteins; GSSP: glutathionylated proteins; oxCys: oxidized cysteine; PC: Principal Component.
Figure 4
Figure 4
Cysteine-related thiols in the kidney cortex and kidney medulla. (A) Total cysteine. (B) Free total cysteine. (C) Free oxidized cysteine. (D) Cysteinylated protein. (E) Free total glutathione/Free total cysteine (Glutathione synthesis). (F) Free total cysteinylglycine/Free total glutathione (Glutathione catabolism). Data are presented as the mean ± standard error of the mean. Wilcoxon matched-pairs signed rank test, ** p < 0.01 and *** p < 0.001. CysGly: cysteinylglycine; CysSSP: cysteinylated proteins; oxCys: oxidized cysteine.
Figure 5
Figure 5
Cysteine metabolism as a source for biomass and bioenergetics. Cys catabolism generates several intermediates that are involved in several metabolic pathways. Through the action of CSE or MST and CAT, besides generating H2S, Cys generates pyruvate, which can supply the TCA cycle and consequently contribute to energy production. Pyruvate can also be converted into alanine and lactate. The products of Cys metabolism can also be deviated to the PPP, which is involved in both nucleotide and amino acid synthesis. In the kidney, the main source of energy is fatty acid β-oxidation, and since the pyruvate resulting from Cys catabolism can also originate acetyl-coA, this suggest Cys as an alternative acetyl-CoA supplier for oxidative phosphorylation and fatty acid synthesis. AA: amino acid; CAT: cysteine aminotransferase; CBS: cystathionine β-synthase; CoA: coenzyme A; CoQ10: coenzyme Q10; CSE: cystathionine γ-lyase; Cys: cysteine; Cyt c: cytochrome c; H2S: hydrogen sulfide; MST: 3-mercapto-pyruvate sulfurtransferase; PPP: pentose phosphate pathway; TCA: tricarboxylic acid. Created with Biorender.com; accessed on 22 January 2022.
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