bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2020‒08‒16
three papers selected by
Thomas Martinez
Salk Institute for Biological Studies


  1. Curr Protoc Bioinformatics. 2020 Sep;71(1): e103
    Brunet MA, Lekehal AM, Roucou X.
      Ten of thousands of open reading frames (ORFs) are hidden within genomes. These alternative ORFs, or small ORFs, have eluded annotations because they are either small or within unsuspected locations. They are found in untranslated regions or overlap a known coding sequence in messenger RNA and anywhere in a "non-coding" RNA. Serendipitous discoveries have highlighted these ORFs' importance in biological functions and pathways. With their discovery came the need for deeper ORF annotation and large-scale mining of public repositories to gather supporting experimental evidence. OpenProt, accessible at https://openprot.org/, is the first proteogenomic resource enforcing a polycistronic model of annotation across an exhaustive transcriptome for 10 species. Moreover, OpenProt reports experimental evidence cumulated across a re-analysis of 114 mass spectrometry and 87 ribosome profiling datasets. The multi-omics OpenProt resource also includes the identification of predicted functional domains and evaluation of conservation for all predicted ORFs. The OpenProt web server provides two query interfaces and one genome browser. The query interfaces allow for exploration of the coding potential of genes or transcripts of interest as well as custom downloads of all information contained in OpenProt. © 2020 The Authors. Basic Protocol 1: Using the Search interface Basic Protocol 2: Using the Downloads interface.
    Keywords:  OpenProt; alt-ORF; alternative ORF; sORF; small ORF
    DOI:  https://doi.org/10.1002/cpbi.103
  2. Redox Biol. 2020 Jul 29. pii: S2213-2317(20)30868-5. [Epub ahead of print] 101663
    Sreekumar PG, Kannan R.
      The mitochondrial-derived peptides (MDPs) are a new class of small open reading frame encoded polypeptides with pleiotropic properties. The prominent members are Humanin (HN) and small HN-like peptide (SHLP) 2, which encode 16S rRNA, while mitochondrial open reading frame of the twelve S c (MOTS-c) encodes 12S rRNA of the mitochondrial genome. While the multifunctional properties of HN and its analog 14-HNG have been well documented, their protective role in the retinal pigment epithelium (RPE)/retina has been investigated only recently. In this review, we have summarized the multiple effects of HN and its analogs, SHLP2 and MOTS-c in oxidatively stressed human RPE and the regulatory pathways of signaling, mitochondrial function, senescence, and inter-organelle crosstalk. Emphasis is given to the mitochondrial functions such as biogenesis, bioenergetics, and autophagy in RPE undergoing oxidative stress. Further, the potential use of HN and its analogs in the prevention of age-related macular degeneration (AMD) are also presented. In addition, the role of novel, long-acting HN elastin-like polypeptides in nanotherapy of AMD and other ocular diseases stemming from oxidative damage is discussed. It is expected MDPs will become a promising group of mitochondrial peptides with valuable therapeutic applications in the treatment of retinal diseases.
    Keywords:  Mitochondria-derived peptides; Mitochondrial function; Nano delivery; Oxidative stress; Retinal pigment epithelium; Signal mechanisms
    DOI:  https://doi.org/10.1016/j.redox.2020.101663
  3. Am J Physiol Endocrinol Metab. 2020 Aug 10.
    Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumaga H, Kim SJ, Lee C.
      Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metabolo-protective properties. The 12S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, while the other seven MDPs, [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes and aging are associated with lower circulating MDPs. Whereas, in humans, muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Further, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell, and to distal tissues, to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metabolo-protective properties of MDPs can be harnessed into therapies for metabolic disease.
    Keywords:  MOTS-c; Mitokine; ageing; mitochondria; mitochondrial derived peptides
    DOI:  https://doi.org/10.1152/ajpendo.00249.2020