A small protein coded within the mitochondrial canonical gene nd4 regulates mitochondrial bioenergetics

BMC Biology

Research Article

Xavier Roucou¹  Jean-François Jacques²  Mathilde Moreau²  Christian R. Landry³  Sophie Breton⁴  Laura Kienzle⁴  Annie Angers⁴  Thierry Choquette⁴  Stefano Bettinazzi⁴  Hajar Hosseini Khorami⁴  Marie Brunet⁵ 

[1] Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS), Sherbrooke, Canada;Département de biochimie et génomique fonctionnelle, Université de Sherbrooke, Sherbrooke, Canada;Département de biochimie et génomique fonctionnelle, Université de Sherbrooke, Sherbrooke, Canada;Département de biochimie, de microbiologie et de bio-informatique, Faculté des sciences et de génie, Université Laval, Québec, Canada;Institut de biologie intégrative et des systèmes, Université Laval, Québec, Canada;PROTEO, Le regroupement québécois de recherche sur la fonction, l’ingénierie et les applications des protéines, Université Laval, Québec, Canada;Centre de recherche sur les données massives, Université Laval, Québec, Canada;Département de biologie, Faculté des sciences et de génie, Université Laval, Québec, Canada;Département de sciences biologiques, Université de Montréal, Montréal, Canada;Service de génétique médicale, Département de pédiatrie, Université de Sherbrooke, Sherbrooke, Canada;Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CRCHUS), Sherbrooke, Canada;

关键词: Mitochondria;    Mitogenome;    Alternative open reading frame;    Mitochondrial proteome;    Protein coding potential;    nd4;    Mitochondrial bioenergetics;    Homo sapiens;   

DOI  :  10.1186/s12915-023-01609-y

 received in 2022-09-17, accepted in 2023-05-03,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMitochondria have a central role in cellular functions, aging, and in certain diseases. They possess their own genome, a vestige of their bacterial ancestor. Over the course of evolution, most of the genes of the ancestor have been lost or transferred to the nucleus. In humans, the mtDNA is a very small circular molecule with a functional repertoire limited to only 37 genes. Its extremely compact nature with genes arranged one after the other and separated by short non-coding regions suggests that there is little room for evolutionary novelties. This is radically different from bacterial genomes, which are also circular but much larger, and in which we can find genes inside other genes. These sequences, different from the reference coding sequences, are called alternatives open reading frames or altORFs, and they are involved in key biological functions. However, whether altORFs exist in mitochondrial protein-coding genes or elsewhere in the human mitogenome has not been fully addressed.ResultsWe found a downstream alternative ATG initiation codon in the + 3 reading frame of the human mitochondrial nd4 gene. This newly characterized altORF encodes a 99-amino-acid-long polypeptide, MTALTND4, which is conserved in primates. Our custom antibody, but not the pre-immune serum, was able to immunoprecipitate MTALTND4 from HeLa cell lysates, confirming the existence of an endogenous MTALTND4 peptide. The protein is localized in mitochondria and cytoplasm and is also found in the plasma, and it impacts cell and mitochondrial physiology.ConclusionsMany human mitochondrial translated ORFs might have so far gone unnoticed. By ignoring mtaltORFs, we have underestimated the coding potential of the mitogenome. Alternative mitochondrial peptides such as MTALTND4 may offer a new framework for the investigation of mitochondrial functions and diseases.

【 授权许可】

CC BY   
© The Author(s) 2023

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