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

BACKGROUND: Mitochondria 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. RESULTS: We 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. CONCLUSIONS: Many 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

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

Abstract Background Mitochondria 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. Results We 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. Conclusions Many 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

Early diagenetic dolomitization and dedolomitization of Late Jurassic and earliest Cretaceous platform carbonates: A case study from the Jura Mountains (NW Switzerland, E France)

Early diagenetic dolomitization is a common feature in cyclic shallow-water carbonates throughout the geologic record. After their generation, dolomites may be subject to dedolomitization (re-calcification of dolomites), e.g. by contact with meteoric water during emersion. These patterns of dolomitization and subsequent dedolomitization frequently play a key role in unravelling the development and history of a carbonate platform. On the basis of excellent outcrops, detailed logging and sampling and integrating sedimentological work, high-resolution sequence stratigraphic interpretations, and isotope analyses (O, C), conceptual models on early diagenetic dolomitization and dedolomitization and their underlying mechanisms were developed for the Upper Jurassic / Lower Cretaceous Jura platform in north-western Switzerland and eastern France. Three different types of early diagenetic dolomites and two types of dedolomites were observed. Each is defined by a distinct petrographic/isotopic signature and a distinct spatial distribution pattern. Different types of dolomites are interpreted to have been formed by different mechanisms, such as shallow seepage reflux, evaporation on tidal flats, and microbially mediated selective dolomitization of burrows. Depending on the type of dolomite, sea water with normal marine to slightly enhanced salinities is proposed as dolomitizing fluid. Based on the data obtained, the main volume of dolomite was precipitated by a reflux mechanism that was switched on and off by high-frequency sea-level changes. It appears, however, that more than one dolomitization mechanism was active (pene)contemporaneously or several processes alternated in time. During early diagenesis, percolating meteoric waters obviously played an important role in the dedolomitization of carbonate rocks that underlie exposure surfaces. Cyclostratigraphic interpretation of the sedimentary succession allows for estimates on the timing of early diagenetic (de)dolomitization. These results are an important step towards a better understanding of the link between high-frequency, probably orbitally forced, sea-level oscillations and early dolomitization under Mesozoic greenhouse conditions