bims-micpro 2025-06-22 papers

Genomics. 2025 Jun 11. pii: S0888-7543(25)00086-2. [Epub ahead of print]117(4): 111070

Landscape of novel smORFs predicted from crop genomes with evolutionary and functional analysis.

Numerous small open reading frames (smORFs) and related smORF-encoded peptides (SEPs) have been identified in model plants. However, a genome-wide overview of smORFs has yet to be established in plants, especially in crops. Here, we predicted millions of novel smORFs in Arabidopsis and 14 commonly cultivated crops by bioinformatic approaches. We found that the smORFs may reflect recurrent polyploidy events and genome rearrangements during evolution, and some smORFs are under strong purifying selection. About 70 % of orthogroups contain SEPs from one species, while 0.1 % of orthogroups contain SEPs from all species. Orthogroup size variation suggests that species-specific features are shaped by factors, including evolutionary relationship, genome size, and genome duplication. DNA repair and translation are major functions of conserved SEPs. Species-specific functions were also observed, such as salt stress responses in Brassica. Our work provides a valuable resource of smORFs and SEPs, offering insights into the understanding of their characteristics.

Keywords: Comparative genomics; Evolutionary analysis; Functional annotation; Microprotein; SEP; smORF

DOI: https://doi.org/10.1016/j.ygeno.2025.111070

Mol Cell Proteomics. 2025 Jun 11. pii: S1535-9476(25)00115-X. [Epub ahead of print] 101016

Identification of Small Open Reading Frame-encoded Peptides in Glioma by an Optimized Proteomics Strategy.

Tingting Zhang, Jian Cheng, Jiao Li, Zixia Ye, Na Li, Jifeng Wang, Xiaojuan Yang, Yong Peng.

Small open reading frame - encoded peptides (SEPs), translated from previously unannotated genomic regions, have emerged as important regulators in diverse physiological and pathological processes. While ribosome profiling and bioinformatics analysis can predict putative SEPs, mass spectrometry (MS) is the only method for their definitive identification. However, MS-based SEP detection faces significant challenges due to SEP's short length and low abundance. To address these limitations, we developed an ammonium formate - mediated C8 solid - phase enrichment (AmF-C8-SPE) strategy that significantly outperforms classic C8-SPE, yielding superior SEP identification with enhanced unique peptide ratios and sequence coverage. By coupling AmF-C8-SPE with fractionation and LC-MS/MS analysis of glioma samples from 18 patients, we identified 549 novel SEPs, 113 of which exhibited differential expression between tumors and adjacent normal tissues. Importantly, randomly selected SEPs were validated by MS spectral matching with synthetic peptides and by confirming recombinant fusion protein expression in cells. Furthermore, Mfuzz clustering and ROC curve analyses revealed SEPs associated with glioma progression. DeepLoc-based prediction followed by confocal microscopy imaging confirmed nuclear localization of two candidate SEPs (IP_613981 and SPROHSA206836). Therefore, this study establishes an optimized SEP identification approach and the first comprehensive SEP profiling in glioma, providing a valuable resource to discover novel glioma biomarker and therapeutic target.

Keywords: Glioma; Mass spectrometry; SEP enrichment; Small open reading frame-encoded peptides (SEPs)

DOI: https://doi.org/10.1016/j.mcpro.2025.101016

Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00466-6. [Epub ahead of print]85(12): 2303-2319.e7

Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma.

Micropeptides, originating from noncanonical translation, represent novel biomolecules with critical roles in tissue homeostasis and cancer development. However, the proteomic landscape and functional mechanisms of micropeptides in hepatocellular carcinoma (HCC) remain largely elusive. By employing a newly devised ultrafiltration tandem mass spectrometry assay, we identified an abundance of micropeptides in clinical HCC samples. Among them, a long non-coding RNA (lncRNA)-derived micropeptide mitochondrial RNase P inhibitory peptide (MRPIP) attenuated HCC progression by modulating the mitochondrial RNA processing machinery. Mechanistically, energy-stress-induced MRPIP hindered mitochondrial ribonuclease P (mtRNase P) complex assembly by interacting with HSD17B10 at the R25 residue, which disrupted the HSD17B10 tetramerization and the subsequent HSD17B10-TRMT10C subcomplex formation, leading to perturbed post-transcriptional RNA processing, translation, energy production in mitochondria, and suppressed cancer progression. Strikingly, the 20-aa functional peptide generated from MRPIP sequences robustly inhibited HCC progression in vitro and in vivo. Overall, our study uncovered and characterized a class of HCC-associated micropeptides, shedding light on cancer diagnosis and treatment.

Keywords: RNA processing; hepatocellular carcinoma; micropeptide; mitochondria

DOI: https://doi.org/10.1016/j.molcel.2025.05.027

Sleep Biol Rhythms. 2025 Jul;23(3): 305-311

Reduced serum levels of mitochondria-derived peptide MOTS-c in patients with obstructive sleep apnea.

Zhuoding Luo, Rui Ji, Renjing Ye, Yawen Shi, Qingfeng Pang, Min Yin.

Recent research has identified the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) as a crucial mitochondrial peptide that significantly influences metabolic regulation, mimics the effects of exercise, and mitigates oxidative stress. This study aims to investigate the relationship between serum MOTS-c levels and obstructive sleep apnea (OSA) to enhance our understanding of the disease's pathophysiology. By elucidating this relationship, we hope to uncover new insights into the mechanisms underlying OSA and its associated metabolic complications. Seventy-seven participants were enrolled in this study, including 53 patients with OSA and 24 controls. We measured serum MOTS-c levels and collected participants' demographic characteristics, polysomnography (PSG) data, complete blood count (CBC) data, and sleep-related questionnaires. The study included 77 participants, consisting of 8 patients with mild OSA, 16 with moderate OSA, 29 with severe OSA, and 24 controls. The cohort comprised 26 women and 51 men. Analysis revealed that serum MOTS-c levels were significantly correlated with BMI, AHI (Apnea-Hypopnea Index), and ODI (Oxygen Desaturation Index), independent of age. Additionally, the severity of OSA was inversely related to serum MOTS-c levels, with lower levels observed in patients with more severe OSA. Variations in serum MOTS-c levels were also noted across different BMI classifications. Analysis of covariance (ANCOVA), with BMI as a covariate, demonstrated that the severity of OSA was an independent factor influencing serum MOTS-c levels. Serum MOTS-c levels correlate with both severity of OSA and BMI classification, suggesting that MOTS-c may have significant therapeutic potential for treating OSA.

Keywords: AHI; BMI; MOTS-c; Obstructive sleep apnea; Oxidative stress

DOI: https://doi.org/10.1007/s41105-025-00578-9

FASEB J. 2025 Jun 30. 39(12): e70734

Aerobic Exercise Upregulates Renal-Derived ELABELA to Improve Myocardial Fibrosis by Activating APJ-AMPK-Sirt1 and Inhibiting TGFβ1-Smad2/3 Signaling Pathways in Myocardial Infarction Mice.

Wujing Ren, Yue Xi, Yixuan Ma, Xinyan Duan, Tianmu Wang, Mengyuan Yu, Shuguang Qin, Da-Wei Gong, Zhenjun Tian.

ELABELA (ELA) has been identified as a potential cardiovascular protective factor. However, the source of endogenous ELA and its molecular mechanism in myocardial fibrosis inhibition remain incompletely understood. Herein, we found that aerobic exercise significantly improved renal apoptosis caused by MI, inhibited inflammation, attenuated structural damage, enhanced renal function, and increased expression and secretion levels of renal ELA. Aerobic exercise stimulated the circulation of renal-derived ELA to reach the MI heart and played a protective role. Under aerobic exercise intervention, renal-specific Elabela overexpression improved myocardial pathological remodeling, decreased cardiomyocyte apoptosis, and enhanced cardiac function. Renal-specific Elabela knockdown significantly increased cardiac apoptosis, inflammation, and fibrosis levels in MI mice, leading to severe impairment of cardiac function. Following AMPK agonist intervention, ELA expression in HKC cells and culture medium increased in a concentration-dependent manner. ELA-14 significantly activated the APJ-AMPK-Sirt1 signaling pathway and inhibited Tgf-β1 transcription by regulating Sirt1 translocation, and AMPK inhibitor weakened ELA-14 function. In cultured cardiac fibroblasts (CFs), the intervention of ELA-14 significantly inhibited the activity of the TGFβ1-Smad2/3 signaling pathway, downregulated the expression of fibrosis-related proteins, increased apoptosis, and lowered the cell migration rate. After TGFβR1 inhibitor intervention, ELA-14 showed a loss of regulation of CFs. Aerobic exercise stimulates the expression of renal-derived ELA, which reaches the MI heart through blood circulation. Renal-derived ELA partly exerts its antifibrotic effects by activating the APJ-AMPK-Sirt1 pathway and inhibiting the TGFβ1-Smad2/3 signaling pathway, contributing to its cardiac protective effects.

Keywords: ELABELA; aerobic exercise; fibrosis; myocardial infarction; renal

DOI: https://doi.org/10.1096/fj.202402897RR