bims-micpro 2026-01-18 papers

Hepatol Commun. 2026 Feb 01. pii: e0885. [Epub ahead of print]10(2):

Mitochondria-derived peptides in liver disease: Emerging regulators of hepatic metabolism and therapeutic targets.

Themis Thoudam, Ge Zeng, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.

Mitochondria-derived peptides (MDPs) are bioactive molecules encoded by small open reading frames within mitochondrial DNA (mtDNA). Humanin, the first MDP to be discovered, functions as a cytoprotective factor, protecting cells from stress-induced apoptosis. Subsequent discoveries expanded this family to include Mitochondrial Open-reading-frame of the Twelve S rRNA-c (MOTS-c), a key regulator of metabolic homeostasis and stress adaptation, and the Small Humanin-Like Peptides (SHLP1-6), which modulate mitochondrial bioenergetics and insulin sensitivity. MDPs play critical roles in liver homeostasis by maintaining mitochondrial function and metabolic balance. Intracellularly, they modulate mitochondrial activity, oxidative stress, and apoptosis, promoting hepatocyte survival. Extracellularly, they act in autocrine, paracrine, or endocrine manners, engaging receptors or signaling pathways to regulate nuclear gene expression and metabolic adaptation. Emerging evidence highlights their relevance in metabolic dysfunction-associated steatotic liver disease (MASLD). Humanin exerts hepatoprotective effects by inhibiting apoptosis and modulating lipid metabolism. MOTS-c activates AMPK, regulates nuclear gene expression, suppresses fibrotic and inflammatory signaling, and restores mitochondrial function in MASLD and fibrosis models. SHLPs, particularly SHLP2, enhance mitochondrial function and insulin sensitivity, supporting glucose homeostasis and mitigating oxidative stress. Collectively, MDPs establish a novel paradigm in mitochondrial signaling, extending mtDNA function beyond energy production. This review summarizes current insights into MDP biology and highlights its emerging therapeutic potential in chronic liver disease.

Keywords: Humanin; Mitochondrial Open-reading-frame of the Twelve S rRNA-c; SHLPs; liver disease; mitochondria-derived peptides; mitochondrial DNA

DOI: https://doi.org/10.1097/HC9.0000000000000885

Genome Biol Evol. 2026 Jan 13. pii: evag005. [Epub ahead of print]

Emergence and tandem repeat-mediated elongation of a translated de novo open reading frame in human oncogenic RNA gene VPS9D1-AS1 (MYU).

Lin Chou, Shu-Ting Cho, Jiwon Lee, David Laub, Douglas Meyer, Hannah Carter, Anne-Ruxandra Carvunis.

New protein-coding genes can arise de novo from ancestrally noncoding regions when open reading frames (ORFs) outside annotated genes are exposed to selection via pervasive translation. These ORFs are usually born short, and their elongation is considered a key step in de novo gene birth. However, mechanisms of de novo gene elongation remain understudied. Here, we reconstructed the evolutionary history of c16riboseqorf143 (orf143), one of the longest unannotated human translated ORFs. orf143 is encoded in the oncogenic long noncoding RNA (lncRNA) VPS9D1-AS1 (MYU). Evolutionary reconstruction showed that orf143 originated de novo in the common ancestor of simians through a point mutation that introduced a start codon. A subsequent stop-codon-disrupting mutation extended translation into a downstream region that, in humans, includes multiple binding sites and a tandem repeat (TR) array previously reported to mediate the oncogenicity of VPS9D1-AS1. The TR array frequently expanded in human populations. The overlaps between orf143 and the oncogenic binding sites in VPS9D1-AS1 raise the possibility that orf143 translation may be tumor-suppressive, since ribosomes may compete with oncogenic binding events via steric hindrance. In line with this possibility, we observed an enrichment of somatic mutations in the ORF regions of VPS9D1-AS1 in cancer patients and a positive association between in-ORF mutations and adenomas/adenocarcinomas. Some of these mutations induced truncation of the ORF, potentially impairing ribosome binding to VPS9D1-AS1. This study reveals stop codon disruption and TR array expansion as the mechanisms of orf143 elongation and illustrates how elongation of de novo ORFs may provide a selective advantage.

Keywords: de novo gene birth; cis-regulation; long noncoding RNA; noncanonical translation

DOI: https://doi.org/10.1093/gbe/evag005

Comput Struct Biotechnol J. 2025 ;27 3704-3709

ChiMSource improves the accuracy of studies on novel amino acid sequences by predicting alternative sources of mass spectrometry-derived peptides.

Umut Çakır, Noujoud Gabed, Ali Yurtseven, Igor Kryvoruchko.

Mass spectrometry (MS) proteomics is currently the most powerful tool for identifying both annotated proteins and proteins translated from non-canonical open reading frames or unusual genetic events. With this method, numerous novel protein-coding loci have been discovered by searching for short fragments of hypothetical longer peptides and polypeptides. Apart from the validation of translation from mRNA transcripts, MS proteomics has been instrumental for the detection of peptides encoded by non-mRNA transcripts. A special application field of MS proteomics is studies on programmed ribosomal frameshifting (PRF), where the detection of chimeric peptides produced from two different reading frames is vital. Each novel chimeric peptide is thought to originate from a certain genetic locus. However, due to the short length of MS peptides, there is a possibility that MS-validated peptides are produced by additional (alternative) loci via PRF. This scenario evaded due attention because the contribution of non-canonical peptides and proteins to the functional diversity of proteomes is still thought to be minor. Recent studies have challenged this paradigm. To the best of our knowledge, our group was the first to include alternative chimeric sources into the analysis pipeline. This resulted in a much higher certainty about the genomic origin of chimeric peptides, which is crucial for their functional characterization. At the same time, our study revealed an enormous diversity of potential alternative sources for a subset of MS-validated chimeric peptides. Here, we present a highly flexible program that predicts alternative chimeric and non-chimeric sources of peptides detected by MS proteomics.

Keywords: Chimeric peptide; alternative open reading frame; mass spectrometry proteomics; mosaic translation; programmed ribosomal frameshifting; proteome

DOI: https://doi.org/10.1016/j.csbj.2025.08.023

Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]

MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.002

RNA. 2026 Jan 12. pii: rna.080824.125. [Epub ahead of print]

Bridging single-molecule and genome-wide studies of cellular mRNA translation.

Adam Koch, Kotaro Tomuro, Taisei Wakigawa, Tatsuya Morisaki, Shintaro J Iwasaki, Timothy J Stasevich.

The translation of mRNA is a tightly regulated, energy-intensive process that drives cellular diversity. Understanding its control requires tools that can capture behavior across scales. Over the past two decades, two complementary techniques have emerged that have transformed our understanding of mRNA translation within cells: ribosome profiling (Ribo-Seq) and live, single-molecule imaging. Ribo-Seq provides genome-wide, codon-level maps of ribosome positions, revealing pause sites, novel open reading frames, and global translation efficiencies. In contrast, live, single-molecule imaging visualizes translation on individual mRNAs in living cells, uncovering heterogeneous initiation, elongation, pausing, and spatial organization in real time. Together, these methods offer complementary strengths - molecular breadth versus temporal and spatial precision - but are rarely applied in tandem. Here, we review their principles, key discoveries, and recent innovations that are bringing them closer together, including endogenous tagging, higher-throughput imaging, absolute calibration, and spatially resolved footprinting. Integrating these approaches promises a unified, multiscale view of translation that connects the dynamics of individual ribosomes to genome-wide patterns of protein synthesis.

DOI: https://doi.org/10.1261/rna.080824.125