Regulation of the ER stress response by a mitochondrial microprotein

Chu, Qian; Martínez, Thomas F.; Novak, Sammy Weiser; Donaldson, Cynthia J.; Tan, Dan; Vaughan, Joan; Chang, Tina; Diedrich, Jolene K.; Andrade, Leonardo R.; Kim, Andrew; Zhang, Tong; Manor, Uri; Saghatelian, Alan

doi:10.1038/s41467-019-12816-z

“…This emerging theme of the preponderance of SEPs in the mitochondria is seen also in the human heart 8 , pointing to the in vivo significance of mito-SEPs in human physiology. When this manuscript was in revision, Saghatelian and colleagues reported the independent discovery of PIGBOS (MSUF1 in this study) as a mitochondrial peptide that mediates the unfolded protein response in the endoplasmic reticulum 44 , underscoring the biological diversity of mito-SEPs. Of high priority is deducing the contribution of the other 14 mito-SEPs to oxidative metabolism.…”

Section: Discussionmentioning

confidence: 79%

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Zhang

¹

,

Reljić

²

,

Liang

³

et al. 2020

View full text Add to dashboard Cite

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. Here, we show that the mitochondrial proteome, particularly the respiratory chain, is enriched for small proteins. Using a prediction and validation pipeline for SEPs, we report the discovery of 16 endogenous nuclear encoded, mitochondrial-localized SEPs (mito-SEPs). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN, a 71 a.a. peptide encoded by C12orf73, is essential for respiratory chain complex III (CIII) assembly. In human cells, BRAWNIN is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In zebrafish, Brawnin deletion causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BRAWNIN is essential for vertebrate oxidative phosphorylation. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

show abstract

“…For instance, phosphatidylinositol glycan anchor biosynthesis class B opposite strand 1 (PIGBOS), a 54aa microprotein, as well as mitochondrial elongation factor 1 microprotein (MIEF1-MP), a 70-aa microprotein, were both located in mitochondrion [24,25]. By merging the results of multiple datasets of normal tissues, our method successfully predicted their subcellular location in mitochondrion (Figure 2a, b).…”

Section: Prediction Of Microprotein Function Based On Expression Simimentioning

confidence: 97%

smORFunction: A Tool for Predicting Functions of Small Open Reading Frames and Microproteins

Ji

¹

,

Cui

²

,

Cui³

2020

Preprint

View full text Add to dashboard Cite

Background Small open reading frame (smORF) is open reading frame with a length of less than 100 codons. Microproteins, translated from smORFs, have been found to participate in a variety of biological processes such as muscle formation and contraction, cell proliferation, and immune activation. Although previous studies have collected and annotated a large abundance of smORFs, functions of the vast majority of smORFs are still unknown. It is thus increasingly important to develop computational methods to annotate the functions of these smORFs. Results In this study, we collected 617,462 unique smORFs from three studies. The expression of smORF RNAs was estimated by reannotated microarray probes. Using a speed-optimized correlation algorism, the functions of smORFs were predicted by their correlated genes with known functional annotations. After applying our method to 5 known microproteins from literatures, our method successfully predicted their functions. Further validation from the UniProt database showed that at least one function of 202 out of 270 microproteins was predicted. Conclusions We developed a method, smORFunction, to provide function predictions of smORFs/microproteins in at most 265 models generated from 173 datasets, including 48 tissues/cells, 82 diseases (and normal). The tool can be available at http://www.cuilab.cn/smorfunction.

show abstract

“…For instance, phosphatidylinositol glycan anchor biosynthesis class B opposite strand 1 (PIGBOS), a 54-aa microprotein, as well as mitochondrial elongation factor 1 microprotein (MIEF1-MP), a 70-aa microprotein, were both located in mitochondrion [24,25]. By merging the results of multiple datasets of normal tissues, our method successfully predicted their subcellular location in mitochondrion ( Fig.…”

Section: Prediction Of Microprotein Function Based On Expression Simimentioning

confidence: 99%

smORFunction: a tool for predicting functions of small open reading frames and microproteins

Ji

¹

,

Cui

²

,

Cui

³

2020

View full text Add to dashboard Cite

Background Small open reading frame (smORF) is open reading frame with a length of less than 100 codons. Microproteins, translated from smORFs, have been found to participate in a variety of biological processes such as muscle formation and contraction, cell proliferation, and immune activation. Although previous studies have collected and annotated a large abundance of smORFs, functions of the vast majority of smORFs are still unknown. It is thus increasingly important to develop computational methods to annotate the functions of these smORFs. Results In this study, we collected 617,462 unique smORFs from three studies. The expression of smORF RNAs was estimated by reannotated microarray probes. Using a speed-optimized correlation algorism, the functions of smORFs were predicted by their correlated genes with known functional annotations. After applying our method to 5 known microproteins from literatures, our method successfully predicted their functions. Further validation from the UniProt database showed that at least one function of 202 out of 270 microproteins was predicted. Conclusions We developed a method, smORFunction, to provide function predictions of smORFs/microproteins in at most 265 models generated from 173 datasets, including 48 tissues/cells, 82 diseases (and normal). The tool can be available at https://www.cuilab.cn/smorfunction.

show abstract

Regulation of the ER stress response by a mitochondrial microprotein

Cited by 143 publications

References 57 publications

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

smORFunction: A Tool for Predicting Functions of Small Open Reading Frames and Microproteins

smORFunction: a tool for predicting functions of small open reading frames and microproteins

Contact Info

Product

Resources

About