bims-micpro 2024-01-07 papers

Mol Cell. 2023 Dec 29. pii: S1097-2765(23)01022-5. [Epub ahead of print]

Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.

Keywords: CRISPR; Ribo-seq; cancer; gene dependency; lncRNAs; medulloblastoma; non-canonical ORFs; translational regulation; uORF

DOI: https://doi.org/10.1016/j.molcel.2023.12.003

Peptides. 2023 Dec 29. pii: S0196-9781(23)00212-7. [Epub ahead of print]172 171147

Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives.

Satadeepa Kal, Sumana Mahata, Suborno Jati, Sushil K Mahata.

Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimer's disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.

Keywords: Diabetes; Humanin; MOTS-c; Mitochondrial peptides; and small humanin-like peptides

DOI: https://doi.org/10.1016/j.peptides.2023.171147

Am J Physiol Endocrinol Metab. 2024 Jan 03.

Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration.

Hiroshi Kumagai, Su-Jeong Kim, Brendan Miller, Toshiharu Natsume, Junxiang Wan, Michi Emma Kumagai, Ricardo Ramirez Ii, Shin Hyung Lee, Ayaka Sato, Hemal H Mehta, Kelvin Yen, Pinchas Cohen.

MOTS-c, a mitochondrial microprotein, has been described as a novel regulator of glucose and lipid metabolism. In addition to its role as a metabolic regulator, MOTS-c prevents skeletal muscle atrophy in high-fat-fed mice. Here, we examined the preventive effect of MOTS-c on skeletal muscle mass using an immobilization-induced muscle atrophy model and explored its underlying mechanisms. Male C57BL/6J mice (10-week-old) were randomly assigned to one of the three experimental groups: non-immobilization control group (sterilized water injection), immobilization control group (sterilized water injection), and immobilization and MOTS-c treated group (15 mg/kg/day MOTS-c injection). We used casting tape for the immobilization experiment. After eight days of the experimental period, skeletal muscle samples were collected and used for the Western blotting, RNA sequencing, lipid, and collagen assays. Immobilization reduced ~15% of muscle mass, while MOTS-c treatment attenuated muscle loss with only a 5% reduction. MOTS-c treatment also normalized phospho-AKT, phospho-FOXO1, and phospho-FOXO3a expression levels, and reduced circulating inflammatory cytokines, such as interleukin-1b (IL-1β), interleukin-6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1), in immobilized mice. An unbiased RNA sequencing and its downstream analyses demonstrated that MOTS-c modified adipogenic-modulating gene expression within the peroxisome proliferator-activated receptors (PPARs) pathway. Supporting this observation, muscle fatty acid levels were lower in the MOTS-c treated group than in the casted-controls. These results suggest that MOTS-c treatment inhibits skeletal muscle lipid infiltration by regulating adipogenesis-related genes and prevents immobilization-induced muscle atrophy.

Keywords: MOTS-c; Mitochondrial microprotein; immobilization; muscle atrophy; myosteatosis

DOI: https://doi.org/10.1152/ajpendo.00285.2023

Mol Psychiatry. 2024 Jan 03.

A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

Su-Jeong Kim, Brendan Miller, Nicolas G Hartel, Ricardo Ramirez, Regina Gonzalez Braniff, Naphada Leelaprachakul, Amy Huang, Yuzhu Wang, Thalida Em Arpawong, Eileen M Crimmins, Penglong Wang, Xianbang Sun, Chunyu Liu, Daniel Levy, Kelvin Yen, Giselle M Petzinger, Nicholas A Graham, Michael W Jakowec, Pinchas Cohen.

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

DOI: https://doi.org/10.1038/s41380-023-02344-0

Plant Cell Environ. 2024 Jan 02.

Small but mighty: Peptides regulating abiotic stress responses in plants.

Tapasya Datta, Ravi S Kumar, Hiteshwari Sinha, Prabodh K Trivedi.

Throughout evolution, plants have developed strategies to confront and alleviate the detrimental impacts of abiotic stresses on their growth and development. The combat strategies involve intricate molecular networks and a spectrum of early and late stress-responsive pathways. Plant peptides, consisting of fewer than 100 amino acid residues, are at the forefront of these responses, serving as pivotal signalling molecules. These peptides, with roles similar to phytohormones, intricately regulate plant growth, development and facilitate essential cell-to-cell communications. Numerous studies underscore the significant role of these small peptides in coordinating diverse signalling events triggered by environmental challenges. Originating from the proteolytic processing of larger protein precursors or directly translated from small open reading frames, including microRNA (miRNA) encoded peptides from primary miRNA, these peptides exert their biological functions through binding with membrane-embedded receptor-like kinases. This interaction initiates downstream cellular signalling cascades, often involving major phytohormones or reactive oxygen species-mediated mechanisms. Despite these advances, the precise modes of action for numerous other small peptides remain to be fully elucidated. In this review, we delve into the dynamics of stress physiology, mainly focusing on the roles of major small signalling peptides, shedding light on their significance in the face of changing environmental conditions.

Keywords: phytohormone; signalling molecule; small peptide

DOI: https://doi.org/10.1111/pce.14792