Two Neuronal Peptides Encoded From a Single Transcript Regulate Mitochondrial Complex III in Drosophila

Authors

Justin A Bosch
Berrak Ugur
Israel Pichardo-Casas
Jordan Rabasco
Felipe Escobedo
Zhongyuan Zuo
Ben Brown
Susan Celniker
David A Sinclair
Hugo J Bellen
Norbert Perrimon

Publication Date

11-8-2022

Journal

eLife

DOI

10.7554/eLife.82709

PMID

36346220

PMCID

PMC9681215

PubMedCentral® Posted Date

11-8-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Drosophila, Electron Transport Complex III, Open Reading Frames, Peptides, Neurons, D. melanogaster

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.