Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

Liang, Chao; Zhang, Shan; Robinson, David R. L.; Ploeg, Matthew Vander; Wilson, Rebecca J.; Nah, Jiemin; Taylor, Dale F.; Beh, Sheryl; Lim, Radiance; Sun, Lei; Muoio, Deborah M.; Stroud, David A.; Ho, Lena

doi:10.1016/j.celrep.2022.111204

Cited by 25 publications

(20 citation statements)

References 58 publications

(72 reference statements)

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“…We propose a model where Sloth1 and Sloth2 peptides are translated from the same transcript, imported into mitochondria where they interact with each other and complex III to promote its assembly ( Figure 10 ). Our results are supported by three recent studies, two published during preparation of this work and one after manuscript submission, in which human Sloth1 (SMIM4) and Sloth2 (C12orf73/Brawnin) were discovered as novel mitochondrial complex III assembly factors in cultured human cells and zebrafish ( Zhang et al, 2020 ; Liang et al, 2022 ; Dennerlein et al, 2021 ).…”

Section: Discussionsupporting

confidence: 85%

“…In addition, our data suggests that Sloth1 and Sloth2 interact in a stoichiometric manner, explaining why single mutants have the same phenotype as double mutants. This is supported by the finding that SMIM4 protein levels are dependent on the presence of C12orf73 and vice versa ( Dennerlein et al, 2021 ; Liang et al, 2022 ). Perhaps maintenance of the proper ratio of Sloth1/2 is an important factor for optimal complex III assembly.…”

Section: Discussionmentioning

confidence: 65%

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

Bosch

Ugur

Pichardo‐Casas

et al. 2022

eLife

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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.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 65%

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

Bosch

Ugur

Pichardo‐Casas

et al. 2022

eLife

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“…Furthermore, the phenotypes obtained are diverse, affecting cell survival, segment fusion or tissue growth, suggesting that smORF peptides are involved in all cellular processes. Indeed, recent studies showed that they can exhibit multiple subcellular localization (Na et al, 2022), with role in, for example, the regulation of calcium flux, the inhibition of protein activity (Jayaram et al, 2021), the antigen presentation (Niu et al, 2020) or the biogenesis of the respiratory chain (Liang et al, 2022). Obviously, further studies are now needed to better understand the function of these smORFs.…”

Section: Discussionmentioning

confidence: 99%

The pleiotropic functions of Pri smORF peptides synchronise leg development regulators

Markus

Pelletier

Boube

et al. 2023

Preprint

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The last decade witnesses the emergence of the abundant family of smORF peptides, encoded by small ORF (<100 codons), whose biological functions remain largely unexplored. Bioinformatic analyses here identify hundreds of putative smORF peptides expressed in Drosophila imaginal leg discs. Thanks to a functional screen in legs, we found smORF peptides involved in morphogenesis, including the pioneer smORF peptides Pri. Since we identified its target Ubr3 in the epidermis and pri was known to control leg development through misunderstood mechanisms, we investigated the role of Ubr3 in mediating pri function in legs. We found that pri play several roles during leg development both in patterning and in cell survival. At larval pupal transition, Pri peptides cooperate with Ubr3 to insure cell survival and leg morphogenesis. Earlier, during larval stage, pri activates independently of Ubr3 tarsal transcriptional programs and Notch and EGFR signalling pathways. Our results highlight Ubr3 dependent and independent functions of Pri peptides and their pleiotropy. Moreover, we reveal that the smORF peptide family is a reservoir of overlooked developmental regulators, displaying distinct molecular functions and orchestrating leg development.

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“…(2020) suggest that exercise might increase BR induction by activation of the AMPK–PGC‐1α axis, it is not unknown whether exercise can induce BR expression or to what extent exercise‐induced physiological adaptations are mediated by BR. Nonetheless, a recent study reported that compared with WT mice, BR KO mice had reduced exercise capacity, as reflected by a decrease in time to exhaustion and maximal running speed (Liang et al., 2022).…”

Section: Introductionmentioning

confidence: 99%

Small peptides: could they have a big role in metabolism and the response to exercise?

Atakan,

Türkel,

Özerkliğ

et al. 2024

The Journal of Physiology

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Exercise is a powerful non‐pharmacological intervention for the treatment and prevention of numerous chronic diseases. Contracting skeletal muscles provoke widespread perturbations in numerous cells, tissues and organs, which stimulate multiple integrated adaptations that ultimately contribute to the many health benefits associated with regular exercise. Despite much research, the molecular mechanisms driving such changes are not completely resolved. Technological advancements beginning in the early 1960s have opened new avenues to explore the mechanisms responsible for the many beneficial adaptations to exercise. This has led to increased research into the role of small peptides (<100 amino acids) and mitochondrially derived peptides in metabolism and disease, including those coded within small open reading frames (sORFs; coding sequences that encode small peptides). Recently, it has been hypothesized that sORF‐encoded mitochondrially derived peptides and other small peptides play significant roles as exercise‐sensitive peptides in exercise‐induced physiological adaptation. In this review, we highlight the discovery of mitochondrially derived peptides and newly discovered small peptides involved in metabolism, with a specific emphasis on their functions in exercise‐induced adaptations and the prevention of metabolic diseases. In light of the few studies available, we also present data on how both single exercise sessions and exercise training affect expression of sORF‐encoded mitochondrially derived peptides. Finally, we outline numerous research questions that await investigation regarding the roles of mitochondrially derived peptides in metabolism and prevention of various diseases, in addition to their roles in exercise‐induced physiological adaptations, for future studies. image

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Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis

Cited by 25 publications

References 58 publications

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

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

The pleiotropic functions of Pri smORF peptides synchronise leg development regulators

Small peptides: could they have a big role in metabolism and the response to exercise?

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