Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status.

Cancer caused 9.9 million deaths in 2020, and natural products and/or their structural analogs represent the greatest number of approved small‐molecules antitumor agents. Benzopyran and quinoline heterocycles have demonstrated cytotoxic activity against different cancer cell lines. Due to its high therapeutic potential, we report the synthesis of 2‐propanamide‐ and 2‐propanamine‐dihydrobenzopyrans bearing different amine moieties in the side chain, as well as the 7‐carbon prenylated derivatives (analogous to natural polyalthidin). Next, we synthesized the 2‐substituted and 2,3‐disubstituted quinolines as benzopyran analogs. We evaluated the cytotoxic activity of all nitrogenated derivatives against human cancer cell lines, including A549 (lung cancer), A2058 (melanoma), HepG2 (hepatocellular carcinoma), MCF‐7 (breast cancer), and Mia PaCa‐2 (pancreas cancer) by the MTT assay. Structure–activity relationship analysis revealed: (i) the benzopyran core was twofold more cytotoxic than quinoline analogs and reached ED ₅₀ values in the low micromolar range (ED ₅₀ < 10 μM) against A2058, HepG2, and MCF‐7; (ii) benzopyran amides showed higher cytotoxicity than benzopyran amines against MCF‐7, and afforded better results for studied lines except for Mia PaCa‐2; and (iii) the amine moiety introduced at 2‐position played a key role for activity; (iv) benzyl and p ‐fluorobenzyl substituents protecting phenol group at 6‐position afforded a similar cytotoxicity.

People with obesity are at high risk to develop metabolic complications such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD). We previously reported that the apoptosis signal-regulating kinase 1 (ASK1) regulates the development of MAFLD, since high fat diet (HFD)-fed mice with liver-specific ASK1 depletion and overexpression revealed increased and blunted development of MAFLD, respectively. Herein we identify a protective role of liver-expressed ASK1 in the context of diet-induced obesity. When fed a HFD for 20 weeks, liver-specific ASK1 overexpressing mice (ASK1 ^+hep ) were resistant to obesity and showed improved glucose metabolism as well as increased energy expenditure compared to control animals. Moreover, HFD-fed ASK1 ^+hep mice had higher BAT activity as well as increased browning of inguinal WAT, as suggested by increased UCP1 levels. The latter may be induced by the hepatokine fibroblast growth factor (FGF21), a hormone that is mainly produced in the liver and is known to reduce body weight via increasing energy expenditure. In line with an important role of FGF21, its plasma levels were significantly increased in HFD-fed ASK1 ^+hep mice and they negatively correlated with body weight. Mechanistically, we propose that the transcription factor ATF4 is activated via HFD-induced ASK1-p38 signaling in hepatocytes, subsequently promoting hepatic Fgf21 gene expression. Supporting this hypothesis, p38 inhibition resulted in a more pronounced reduction in Fgf21 expression in ASK1 ^+hep hepatocytes compared to controls, while silencing of ATF4 in primary hepatocytes significantly decreased Fgf21 transcript levels in ASK1 ^+hep hepatocytes but not in hepatocytes derived from control mice. In conclusion, we have uncovered a yet undescribed axis between hepatic ASK1 and FGF21 which positively affects body weight and glucose metabolism.