bims-micpro 2026-01-04 papers

Int J Mol Sci. 2025 Dec 09. pii: 11883. [Epub ahead of print]26(24):

Microproteins in Metabolic Biology: Emerging Functions and Potential Roles as Nutrient-Linked Biomarkers.

Microproteins are small polypeptides translated from short open reading frames (sORFs) that typically encode < 100 amino acids. Advances in ribosome profiling, mass spectrometry, and computational prediction have revealed a growing number of microproteins that play important roles in cellular metabolism, organelle function, and stress adaptation; however, these were considered non-coding or functionally insignificant. At the mitochondrial level, microproteins, such as MTLN (also known as mitoregulin/MOXI) and BRAWNIN, contribute to lipid oxidation, oxidative phosphorylation efficiency, and respiratory chain assembly. Other microproteins at the endoplasmic reticulum-mitochondria interface, including PIGBOS and several muscle-resident regulators of calcium cycling, show diverse biological contexts in which these microproteins act. A subset of microproteins responds to nutrient availability. For example, SMIM26 modulates mitochondrial complex I translation under serine limitation, and non-coding RNA expressed in mesoderm-inducing cells encoded with peptides facilitates glucose uptake during differentiation, indicating that some microproteins can affect metabolic adaptation through localized translational- or organelle-level mechanisms. Rather than functioning as primary nutrient sensors, these microproteins complement classical nutrient-responsive pathways such as AMP-activated protein kinase-, peroxisome proliferator-activated receptor-, and carbohydrate response element binding protein-mediated signaling. As the catalog of microproteins continues to expand, integrating proteogenomics, nutrient biology, and functional studies will be central to defining their physiological relevance; these integrative approaches will also help reveal their potential applications in metabolic health.

Keywords: metabolic disorder; metabolic reprogramming; microproteins; mitochondrial regulation; nutrient sensing; obesity; precision nutrition; type 2 diabetes

DOI: https://doi.org/10.3390/ijms262411883

World J Gastrointest Oncol. 2025 Dec 15. 17(12): 112753

Interlaced roles of mitochondrial DNA in colorectal cancer: Liquid-biopsy biomarkers, nuclear mtDNA-driven genomic instability, and mito-encoded micro peptide signaling.

Thai-Hau Koo, Xue-Bin Leong, Yi-Lin Lee, Firdaus Hayati, Andee Dzulkarnaen Zakaria.

Colorectal cancer (CRC) is a widely occurring malignancy with significant mortality on a global scale, making up close to 10% of all diagnosed cancers in 2020. While traditional CRC diagnostics and research have focused on nuclear genomic alterations, emerging evidence has highlighted the multifaceted roles of mitochondrial DNA (mtDNA) in the pathogenesis and clinical management of CRC. In this review, we examine three interlaced aspects of mtDNA in CRC: (1) Liquid biopsy biomarkers: Cell-free mtDNA circulating in the blood serving as a minimally invasive diagnostic and monitoring tool; (2) Nuclear mtDNA (NUMT)-driven genomic instability: The somatic nuclear incorporation of mtDNA (NUMT segments, or NUMT), contributing to mutational burden and chromosomal disruption in tumours; and (3) Mitochondria-encoded micropeptide signaling - small peptides encoded by the mtDNA that modulate cellular pathways and tumour behaviour. Recent high-impact studies have demonstrated that tumour-derived mtDNA in biofluids can augment cancer detection sensitivity, although technical challenges remain due to mtDNA fragmentation and background noise. Meanwhile, genomic analyses have uncovered a significant increase in NUMT insertion events in CRC cells, linking mitochondrial genome escape to nuclear genome instability and identifying potential numtogenesis suppressor genes. A novel dimension of mito-nuclear interactions in cancer was discovered in mitochondrial microproteins, such as humanin and mitochondrial open reading frame of the 12S rRNA type-c. Humanin exhibits both tumour-promoting and cytoprotective properties under specific conditions, while mitochondrial open reading frame of the 12S rRNA type-c possesses tumour-suppressive activities under other conditions. The outcomes of clinical, mechanistic, and translational research, revealing how mtDNA-based biomarkers and involvement contribute towards early detection, prognostication, and treatment of CRC, are presented.

Keywords: Biomarker discovery; Gastrointestinal malignancy; Multi-omics; Precision oncology; Proteomic; Therapeutic resistance

DOI: https://doi.org/10.4251/wjgo.v17.i12.112753

J Biol Chem. 2025 Dec 27. pii: S0021-9258(25)02964-3. [Epub ahead of print] 111112

The long non-coding RNA MALAT1 encodes a micropeptide that promotes influenza A virus replication by suppressing innate immune responses.

Kul Raj Rai, Faxin Wen, Mohamed Maarouf, Mengjuan Cai, Haowen Sun, Zhihui Yin, Yiming Wang, Xiaojuan Chi, Yongxia Li, Yuhai Chen, Prasha Shrestha, Zhou Yang, Shile Huang, Song Wang, Ji-Long Chen.

Long non-coding RNAs (lncRNAs) play critical roles in diverse biological processes and contain structurally distinct domains enabling multifunctional activity. Viral infections dynamically regulate lncRNA expression, leading to modulation of key cellular pathways, including innate immune responses. MALAT1, an important lncRNA, exerts diverse biological functions through specific RNA motifs; however, its role in influenza A virus (IAV) infection and pathogenesis remains largely unexplored. Here, we investigated the regulation of MALAT1 expression and its role during the IAV infection. We found that IAV infection robustly upregulated the expression of MALAT1 in vitro and in vivo. The IAV-induced MALAT1 expression was independent of interferon signaling. Furthermore, we demonstrated that MALAT1 expression was regulated via the NF-κB/IL-6/STAT3 pathway in host cells infected with IAV. Functional studies revealed that disruption of MALAT1 expression inhibited IAV replication, whereas overexpression of certain MALAT1 fragments enhanced the virus replication. Using ribosome profiling, mass spectrometry, and antibody validation, we identified a 52-amino acid micropeptide (miPEP-52) encoded by an RNA fragment of MALAT1, which was endogenously expressed and upregulated by IAV infection. Moreover, we observed that miPEP-52 strongly enhanced the replication of IAV, including attenuated strains. Mutating the miPEP-52 start codon or deleting its coding sequence from the MALAT1 RNA fragment abolished these effects. Mechanistically, MALAT1 and the RNA fragment of MALAT1 encoding miPEP-52 significantly suppressed innate immune responses to IAV infection. These findings provide new insights into the role of MALAT1 in viral pathogenesis and suggest a strategy by which virus evades host antiviral innate immunity.

Keywords: Influenza A virus; MALAT1; innate immunity; lncRNA; micropeptide

DOI: https://doi.org/10.1016/j.jbc.2025.111112

Cureus. 2025 Nov;17(11): e98204

Serum Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) Dynamics as a Complementary Marker of Treatment Response in Newly Diagnosed Multiple Myeloma: A Prospective Analysis.

Veysel Erol, Esin Avci, Sibel Kabukcu Hacioglu, Nil Guler, Gulsum Akgun Cagliyan, Başak Ünver Koluman, Ismail Can Kendir, Ozde Elver, Kayihan Kara, Erhan Kaya, Nevin Alayvaz Aslan.

OBJECTIVES: This study evaluated whether serum levels of mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) could provide prognostic insights in patients newly diagnosed with multiple myeloma (MM), particularly in relation to therapeutic responsiveness.
METHODS: In a prospective analysis involving 29 MM patients, serum MOTS-c concentrations were measured before and after frontline treatment. Associations between MOTS-c fluctuations and clinical-biochemical variables were systematically explored.
RESULTS: Patients who responded to treatment exhibited a substantial post-therapy increase in MOTS-c levels, while refractory cases showed little to no change. Post-treatment MOTS-c values inversely correlated with calcium and neutrophil count changes. Despite limited standalone predictive capacity, MOTS-c dynamics may reflect microenvironmental and metabolic adaptation linked to treatment response.
CONCLUSIONS: Changes in serum MOTS-c concentrations following therapy may serve as complementary markers of clinical response in MM. Further validation in larger cohorts is warranted.

Keywords: mitochondrial peptide; molecular biomarker; mots-c; multiple myeloma prognosis; treatment response

DOI: https://doi.org/10.7759/cureus.98204

Pathol Res Pract. 2025 Dec 23. pii: S0344-0338(25)00537-0. [Epub ahead of print]278 156344

Mitochondrial-derived microproteins in cancer and neurodegeneration: A new era of cross-disease mechanistic insights.

Shangtong Hu, Chunxiu Hu, Minfeng Tong.

Mitochondrial-derived microproteins (MDPs) translate mitochondrial stress into cellular decisions that shape aging, metabolism, cancer biology, and neurodegeneration. Humanin, MOTS-c, SHLPs, and the recently identified SHMOOSE act through distinct intracellular and receptor-mediated pathways to regulate apoptosis, nutrient sensing, redox balance, and mito-nuclear communication. These programs confer neuroprotection in post-mitotic tissues but can be co-opted by tumors for survival, invasion, and therapy resistance, helping explain the inverse comorbidity between cancer and Alzheimer's disease. This review synthesizes the divergent signaling architectures of major MDPs, including Humanin-FPR2/gp130, MOTS-c-AMPK/NRF2-LARS1/mTORC1, SHLP2-CXCR7, and SHMOOSE's genotype-dependent activity, and outlines how these mechanisms produce disease-specific outcomes. Recent advances in mitoribosome profiling, DIA-based proteogenomics, and mitochondrial base editing have accelerated the discovery and functional characterization of MDPs. Emerging translational opportunities include MDP-targeted agonists, antagonists, and engineered delivery systems designed for application in neurodegenerative disorders and cancer. Overall, MDPs represent a druggable signaling layer whose context-dependent effects can be selectively directed across diseases.

Keywords: Cancer-neurodegeneration crosstalk; Humanin; MOTS-c; MTORC1-LARS1 axis; Mitochondrial-derived microproteins (MDPs)

DOI: https://doi.org/10.1016/j.prp.2025.156344