bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2026–01–25
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Mitochondrial-Derived Microproteins in Lung Disease: Insights and Implications.
  2. Community benchmarking and evaluation of human unannotated microprotein detection by mass spectrometry based proteomics.
  3. Systematic Analysis of C-Termini of Small Open Reading Frame-Encoded Peptides in Human Cancer Cell Lines.
  4. Modulating splicing in 5' untranslated regions to treat rare haploinsufficient disease.
  5. Poor man's ribo-seq: circa 1968.
  6. Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss.
  7. Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
  1. Am J Physiol Lung Cell Mol Physiol. 2026 Jan 22.
    Mitochondrial-Derived Microproteins in Lung Disease: Insights and Implications.
    Molly Behan, Kelvin Yen, Pinchas Cohen, Corrine R Kliment.
      As bioactive microproteins, Mitochondrial-Derived-MicroProteins (MDPs) are encoded within the small open reading frames (sORFs) of mitochondrial DNA. MDPs have been shown to be altered in a number of disease states and have mitochondrial, nuclear and extracellular actions. Most published work on MDP's has focused on MOTS-c and Humanin's actions in tissues with high mitochondrial density (heart, skeletal muscle, and brain) or in disease states of advanced age - Alzheimer's, Cancer, Cardiovascular disease. This review aims to highlight the existing gaps in knowledge related to MDPs' role in lung homeostasis and disease - including Acute Lung Injury (ALI), Chronic Obstructive Pulmonary Disease (COPD), allergic asthma (AA) and Pulmonary Fibrosis (PF). The increasingly recognized role of MDPs in non-pulmonary diseases sheds light on the importance of more investigations of MDPs, their clinical and mechanistic roles, and their therapeutic potential for pulmonary diseases.
    Keywords:  COPD; acute lung injury; microproteins; mitochondria; pulmonary fibrosis
    DOI:  https://doi.org/10.1152/ajplung.00369.2025
  2. Nat Commun. 2026 Jan 21.
    Community benchmarking and evaluation of human unannotated microprotein detection by mass spectrometry based proteomics.
    Aaron Wacholder, Eric W Deutsch, Leron W Kok, Jip T van Dinter, Jiwon Lee, James C Wright, Sebastien Leblanc, Ayodya H Jayatissa, Kevin Jiang, Ihor Arefiev, Kevin Cao, Francis Bourassa, Felix-Antoine Trifiro, Michal Bassani-Sternberg, Pavel V Baranov, Annelies Bogaert, Sonia Chothani, Ivo Fierro-Monti, Daria Fijalkowska, Kris Gevaert, Norbert Hubner, Jonathan M Mudge, Jorge Ruiz-Orera, Jana Schulz, Juan Antonio Vizcaíno, John R Prensner, Marie A Brunet, Thomas F Martinez, Sarah A Slavoff, Xavier Roucou, Jyoti S Choudhary, Sebastiaan van Heesch, Robert L Moritz, Anne-Ruxandra Carvunis.
      Thousands of short open reading frames (sORFs) are translated outside of annotated coding sequences. Recent studies have pioneered searching for sORF-encoded microproteins in mass spectrometry (MS)-based proteomics and peptidomics datasets. Here, we assessed literature-reported MS-based identifications of unannotated human proteins. We find that studies vary by three orders of magnitude in the number of unannotated proteins they report. Of nearly 10,000 reported sORF-encoded peptides, 96% were unique to a single study, and 12% mapped to annotated proteins or proteoforms. Manual curation of a benchmark dataset of 406 manually evaluated spectra from 204 sORF-encoded proteins revealed large variation in peptide-spectrum match (PSM) quality between studies, with immunopeptidomics studies generally reporting higher quality PSMs than conventional enzymatic digests of whole cell lysates. We estimate that 65% of predicted sORF-encoded protein detections in immunopeptidomics studies were supported by high-quality PSMs versus 7.8% in non-immunopeptidomics datasets. Our work stresses the need for standardized protocols and analysis workflows to guide future advancements in microprotein detection by MS towards uncovering how many human microproteins exist.
    DOI:  https://doi.org/10.1038/s41467-025-68002-x
  3. J Proteome Res. 2026 Jan 22.
    Systematic Analysis of C-Termini of Small Open Reading Frame-Encoded Peptides in Human Cancer Cell Lines.
    Mingbo Peng, Tianjing Wang, Yajiao Fan, Jianyi Zhou, Cuihong Wan.
      The C-termini often regulate protein biological functions through specific structures or modifications. Small open reading frame-encoded peptides (SEPs) make up a novel class of gene expression products that participate in various biological activities. Their C-termini have also been found to affect their function, but the polymorphism of SEPs' C-termini has not yet been systematically elucidated. Using C-terminal proteomics, we identified 3636 C-terminal peptides from 2168 proteins in three human cancer cell lines, including 3364 peptides from 1901 classical proteins and 272 peptides from 267 SEPs. Approximately 20% of all of the identified C-terminal peptides had been reported in previous studies, originating from mRNA alternative splicing or protease cleavage, while more than 85% of the C-terminal peptides from SEPs were novel. Bioinformatics analysis revealed that most new SEP C-termini are likely produced by protease cleavage by the KLK, MMP, and CAT protease families. Others without accurately predicted hydrolysis sites may originate from alternative splicing or protein trimming. The intact and hydrolysis products of some SEPs were verified by immunoblotting. Some cleavage occurs in the predicted domain, which might affect SEPs' function. This study enriches the SEP sequence information, provides experimental evidence for SEP in vivo processing, and supports the subsequent functional analysis of SEP.
    Keywords:  C-terminomics; alternative splicing; proteolytic; sORF-encoded peptides; truncate
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00756
  4. bioRxiv. 2025 Dec 09. pii: 2025.12.07.692584. [Epub ahead of print]
    Modulating splicing in 5' untranslated regions to treat rare haploinsufficient disease.
    Eloise S Beer Wells, Laura De Conti, Hyung Chul Kim, Narjes Rohani, Kartik Chundru, Laura M Watts, Ruebena Dawes, Yuyang Chen, Alexandra C Martin-Geary, Michael J Griffiths, Sam Scott, Rosemary A Bamford, Jonathan Mill, Caroline F Wright, Marco Baralle, Stephan J Sanders, Nicola Whiffin.
      Rare genetic disorders collectively impact over 300 million people worldwide, yet around 95% have no specific treatments. For the many rare disorders caused by haploinsufficiency, effective therapies need to upregulate protein expression. However, therapeutic upregulation is often not straightforward. Increasing protein translation of the wildtype allele through inhibiting repressive upstream open reading frames (uORFs) has been proposed as a therapeutic approach for a few specific genes. The widespread success of steric-block antisense oligonucleotides (ASOs) for this purpose is, however, debated. Here, we explore an alternative approach, using splice-switching to exclude uORF-containing exons from the mRNA. Through a genome-wide computational screening approach, we identified 79 uORF-containing 5'UTR exons in haploinsufficient monogenic disease genes as candidate exon skipping targets. We demonstrate that removing the target exon significantly increased protein translation (between 1.4-5.5 fold) in a luciferase reporter assay for four of six prioritised target 5'UTR exons in neurodevelopmental disorder genes ( CTCF , GRIN2B , KRIT1 , and TSC1 ). Overall, this work supports the widespread application of 5'UTR exon skipping to boost translation of clinically relevant haploinsufficient genes.
    DOI:  https://doi.org/10.64898/2025.12.07.692584
  5. Open Biol. 2026 Jan 21. pii: 250392. [Epub ahead of print]16(1):
    Poor man's ribo-seq: circa 1968.
    Tony Hunter.
      
    Keywords:  globin; haemoglobin; mRNA; reticulocyte; ribosome profiling
    DOI:  https://doi.org/10.1098/rsob.250392
  6. J Clin Transl Endocrinol. 2026 Feb;43 100429
    Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss.
    Se-Hee Yoon, Fei Yuan, Xiangyang Zhu, Hui Tang, Dilbar Abdurakhimoova, James Krier, Alfonso Eirin, Amir Lerman, Pinchas Cohen, Lilach O Lerman.
       Introduction: MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived peptide and regulator of metabolic homeostasis. Although its role in glucose and lipid metabolism is emerging, changes in circulating MOTS-c with obesity remain unclear. We hypothesized that circulating MOTS-c concentrations would be altered in obese vs. lean adults in associations with altered metabolic and inflammatory markers.
    Methods: Circulating MOTS-c levels, metabolic parameters, and inflammatory markers were compared between 22 lean controls and 32 obese participants scheduled for bariatric surgery. Longitudinal changes in weight, MOTS-c levels, and metabolic markers were also analyzed in 10 of the obese patients before and 6 months after bariatric surgery. Additionally, adipose tissue MOTS-c expression was assessed by immunofluorescence in lean kidney donors (n = 6) and obese (n = 14) subjects.
    Results: Circulating MOTS-c levels were significantly higher in obese compared to lean individuals (273 ± 56 vs. 223 ± 50 pg/mL; P < 0.01). BMI and HOMA-IR independently predicted elevated MOTS-c levels (P = 0.035 and P = 0.032, respectively). MOTS-c showed a biphasic relationship with HOMA-IR, rising sharply above HOMA-IR of ∼ 6.6 mmol/L×µU/mL. Adipose tissue MOTS-c did not differ between the groups or correlate with circulating MOTS-c. Despite significant BMI improvements post-surgery (P < 0.001), circulating MOTS-c levels remained unchanged (P = 0.913).
    Conclusion: Circulating MOTS-c levels are elevated in obesity, exhibiting a nonlinear relationship with BMI and insulin resistance. MOTS-c may represent a compensatory metabolic response in obesity and insulin-resistant states, highlighting its potential as a clinical biomarker. This preliminary exploratory study warrants validation in larger and independent cohorts.
    Keywords:  MOTS-c; Metabolic dysregulation; Obesity
    DOI:  https://doi.org/10.1016/j.jcte.2025.100429
  7. Cardiovasc Res. 2026 Jan 20. pii: cvag011. [Epub ahead of print]
    Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
    Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau.
       AIMS: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.
    METHODS AND RESULTS: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.
    CONCLUSION: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.
    Keywords:  Cyb5r3; cardiolipin; cardioprotection; cristae; docosahexaenoic acid; ischemia-reperfusion; mitochondria; monolysocardiolipin; permeability transition; triglycerides
    DOI:  https://doi.org/10.1093/cvr/cvag011
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