BRAWNIN: A sORF-encoded Peptide Essential for Vertebrate Mitochondrial Complex III Assembly

Abstract

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution 1,2 . Here, we show that the mitochondria proteome is enriched for proteins smaller than 100 a.a. (defined as SEPs). Using a mitochondrial prediction and validation pipeline for small open-reading-frame(sORF)-encoded peptides (SEPs), we report the discovery of 16 endogenous mitochondrial SEPs (mito-SEPs) associated with oxidative phosphorylation (OXPHOS). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment

“…In cancer cells, glycolysis is facilitated by the Warburg effect, which is a hallmark feature of all cancers, and OXPHOS is suppressed (Balsa et al, 2020;Koppenol et al, 2011;Zhang et al, 2020). However, several human tumors such as glioblastoma and leukemia mainly depend on OXPHOS and not glycolysis for energy generation, leading to the formation of a hypoxic TME, which can be exploited for cancer therapy (DeBerardinis and Chandel, 2020; Hensley et al, 2016;Kennedy et al, 2013).…”

Mapping subcellular localizations of unannotated microproteins and alternative proteins with MicroID

“…It is now known that thousands of smORFs and alt-ORFs are translated in eukaryotic cells (Brunet et al, 2021b;Martinez et al, 2020;Orr et al, 2020;Slavoff et al, 2013). Microproteins and alt-proteins regulate important cellular and physiological processes in diverse organisms, including DNA repair (Arnoult et al, 2017), transcription (Koh et al, 2021), and innate immunity (Jackson et al, 2018), among others (Cao et al, 2021;Huang et al, 2021;Lee et al, 2021;Zhang et al, 2020). Microproteins GREP1 (Prensner et al, 2021), CASIMO1 (Polycarpou-Schwarz et al, 2018), and MP31 (Huang et al, 2021) are associated with cancer, and alt-FUS (Brunet et al, 2021a) may contribute to amyotrophic lateral sclerosis-associated protein aggregation.…”