Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila

  1. Justin A Bosch  Is a corresponding author
  2. Berrak Ugur
  3. Israel Pichardo-Casas
  4. Jordan Rabasco
  5. Felipe Escobedo
  6. Zhongyuan Zuo
  7. Ben Brown
  8. Susan Celniker
  9. David A Sinclair
  10. Hugo J Bellen
  11. Norbert Perrimon  Is a corresponding author
  1. Harvard University, United States
  2. Howard Hughes Medical Institute, Yale University, United States
  3. Baylor College of Medicine, United States
  4. Lawrence Berkeley National Laboratory, United States

Abstract

Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of genes.

Data availability

The current manuscript did not generate any datasets. Raw gel and western image source files are present in Supplemental File 4, which can be downloaded at:https://doi.org/10.5061/dryad.83bk3j9vc

The following data sets were generated

Article and author information

Author details

  1. Justin A Bosch

    Department of Genetics, Harvard University, Boston, United States
    For correspondence
    jabosch@hms.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8499-1566
  2. Berrak Ugur

    Department of Neuroscience, Howard Hughes Medical Institute, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4806-8891
  3. Israel Pichardo-Casas

    Department of Genetics, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
  4. Jordan Rabasco

    Department of Genetics, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
  5. Felipe Escobedo

    Department of Genetics, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6830-9210
  6. Zhongyuan Zuo

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Ben Brown

    Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Susan Celniker

    Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, United States
    Competing interests
    No competing interests declared.
  9. David A Sinclair

    Department of Genetics, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
  10. Hugo J Bellen

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5992-5989
  11. Norbert Perrimon

    Department of Genetics, Harvard University, Boston, United States
    For correspondence
    perrimon@genetics.med.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7542-472X

Funding

Damon Runyon Foundation

  • Justin A Bosch

National Institutes of Health (R01GM084947)

  • Susan Celniker

National Institutes of Health (R01GM067761)

  • Susan Celniker

National Institutes of Health (R24OD019847)

  • Susan Celniker

National Institutes of Health (NHGRI HG009352)

  • Susan Celniker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Agnieszka Chacinska, IMol Polish Academy of Sciences, Poland

Version history

  1. Preprint posted: July 2, 2020 (view preprint)
  2. Received: August 15, 2022
  3. Accepted: November 1, 2022
  4. Accepted Manuscript published: November 8, 2022 (version 1)
  5. Version of Record published: November 22, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Justin A Bosch
  2. Berrak Ugur
  3. Israel Pichardo-Casas
  4. Jordan Rabasco
  5. Felipe Escobedo
  6. Zhongyuan Zuo
  7. Ben Brown
  8. Susan Celniker
  9. David A Sinclair
  10. Hugo J Bellen
  11. Norbert Perrimon
(2022)
Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila
eLife 11:e82709.
https://doi.org/10.7554/eLife.82709

Share this article

https://doi.org/10.7554/eLife.82709

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