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Mitochondrial dysfunction plays an important role in acute kidney injury (AKI). Thus, the agents improving the mitochondrial function could be beneficial for treating AKI. Ursodeoxycholic acid (UDCA) has been demonstrated to prevent mitochondrial dysfunction under pathology, however, its role in AKI and the underlying mechanism remain unknown. This study aimed to evaluate the effect of UDCA on cisplatin-induced AKI. In vivo , C57BL/6 J mice were treated with cisplatin (25 mg/kg) for 72 h to induce AKI through a single intraperitoneal (i.p.) injection with or without UDCA (60 mg/kg/day) administration by gavage. Renal function, mitochondrial function and oxidative stress were analyzed to evaluate kidney injury. In vitro , mouse proximal tubular cells (mPTCs) and human proximal tubule epithelial cells (HK2) were treated with cisplatin with or without UDCA treatment for 24 h. Transcriptomic RNA-seq was preformed to analyze possible targets of UDCA. Our results showed that cisplatin-induced increments of serum creatinine (Scr), blood urea nitrogen (BUN), and cystatin C were significantly reduced by UDCA along with ameliorated renal tubular injury evidenced by improved renal histology and blocked upregulation of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1). Meanwhile, the apoptosis induced by cisplatin was also markedly attenuated by UDCA administration. In vitro , UDCA treatment protected against tubular cell apoptosis possibly through antagonizing mitochondrial dysfunction and oxidative stress by targeting ALDH1L2 which was screened out by an RNA-seq analysis. Knockout of ALDH1L2 by CRISPR/Cas9 greatly blunted the protective effects of UDCA in renal tubular cells. Moreover, UDCA did not diminish cisplatin's antineoplastic effect in human cancer cells. In all, our results demonstrated that UDCA protects against cisplatin-induced AKI through improving mitochondrial function through acting on the expression of ALDH1L2, suggesting a clinical potential of UDCA for the treatment of AKI. Image 1 • Ursodeoxycholic acid (UDCA) ameliorated cisplatin-induced acute kidney injury. • UDCA protected against cisplatin-induced mitochondrial dysfunction. • UDCA protected against redox imbalance induced by cisplatin in renal tubule cells through acting on ALDH1L2. [ABSTRACT FROM AUTHOR]

[Display omitted] • The germline variants analysis from alcohol metabolism pathway genes obtained a significant variant in the ALDH1L2 gene (rs199841702) found to associate with alcoholic liver disease. • Most of the available online in-silico Pathogenicity prediction tools predicted ALDH1L2 (c.337C > G, p.Pro113Ala) gene variant as 'deleterious' and 'pathogenic'. • The presence of the GC genotype in ALDH1L2 (rs19984170)polymorphism may indicate an increased risk of developing ALD. The pathogenetic events of liver disease are seemingly determined by factors linked to ethanol metabolism. The variations in genes encoding enzymes of the ethanol metabolic pathway can influence exposure to alcohol and thus may act as risk factors for the development of liver disease. The present study aimed to understand the genetic aspect of germline variations in ethanol metabolic pathway genes in two major categories of liver disease i.e. ALD and NAFLD. Targeted Re-sequencing was performed in the two disease categories along with healthy control followed by an assessment and evaluation of the variants in a case vs control manner. The pathogenicity prediction was evaluated using SIFT, PolyPhen, PROVEN, LRT, CADD, FATHMM, EIGEN, REVEL and VarSome, while MD simulation of a novel significant variant was performed using the GROMACS 5.1.4 package. The annotation of targeted re-sequencing results revealed 2172 variants in different locations of the genes. Upon recurrent assessment predominantly focusing on exonic missense variants from these genes of the alcohol metabolism pathway, the ALDH1L2 [c.337C > G, p.Pro113Ala, (rs199841702)] variant was found highly significant with comprehensive results. The amino acid substitution tool that predicted protein stability due to a point mutation showed a decrease in stability. The genotyping distribution of the identified novel variant in the population revealed that heterozygosity is significantly distributed in ALD patients. However, the predominant association between the inherited variant and the cause of developing disease needs further robust study. [ABSTRACT FROM AUTHOR]

Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes—aldehyde dehydrogenase 1 family member 2 (ALDH1L2)—produces NADPH by catabolizing 10-formyl-THF into CO 2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling. [Display omitted] • Loss of ALDH1L2 increases formate and formyl-methionine production • ALDH1L2 levels influence migration in a formyl-peptide receptor-dependent manner • In the primary tumor, ALDH1L2 levels impact metastatic capacity Hennequart et al. describe the role of ALDH1L2, a mitochondrial enzyme involved in one-carbon metabolism, in breast cancer cells. Loss of ALDH1L2 leads to increased production of formate and formyl-methionine, promoting an increase in migration that is dependent on the formyl-peptide receptor and enhancing metastasis in vivo. [ABSTRACT FROM AUTHOR]

Abstract: 10-Formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1), an abundant cytosolic enzyme of folate metabolism, shares significant sequence similarity with enzymes of the aldehyde dehydrogenase (ALDH) family. The enzyme converts 10-formyltetrahydrofolate (10-fTHF) to tetrahydrofolate and CO2 in an NADP+-dependent manner. The mechanism of this reaction includes three consecutive steps with the final occurring in an ALDH-homologous domain. We have recently identified a mitochondrial isoform of FDH (mtFDH), which is the product of a separate gene, ALDH1L2. Its overall identity to cytosolic FDH is about 74%, and the identity between the ALDH domains rises up to 79%. In the present study, human mtFDH was expressed in Escherichia coli, purified to homogeneity, and characterized. While the recombinant enzyme was capable of catalyzing the 10-fTHF hydrolase reaction, it did not produce detectable levels of ALDH activity. Despite the lack of typical ALDH catalysis, mtFDH was able to perform the characteristic 10-fTHF dehydrogenase reaction after reactivation by recombinant 4′-phosphopantetheinyl transferase (PPT) in the presence of coenzyme A. Using site-directed mutagenesis, it was determined that PPT modifies mtFDH specifically at Ser375. The C-terminal domain of mtFDH (residues 413–923) was also expressed in E. coli and characterized. This domain was found to exist as a tetramer and to catalyze an esterase reaction that is typical of other ALDH enzymes. Taken together, our studies suggest that ALDH1L2 has enzymatic properties similar to its cytosolic counterpart, although the inability to catalyze the ALDH reaction with short-chain aldehyde substrates remains an unresolved issue at present. [Copyright &y& Elsevier]