Structural characterization of mitoribosome during translation of COX protein
Title: Structural characterization of mitoribosome during translation of COX protein
DNr: Berzelius-2023-129
Project Type: LiU Berzelius
Principal Investigator: Minh Duc Nguyen <>
Affiliation: Karolinska Institutet
Duration: 2023-06-29 – 2024-01-01
Classification: 10601


Mitochondria are essential organelles in all eukaryotes, generating ATP via the oxidative phosphorylation (OXPHOS) pathway, thus providing energy to the cell. Moreover, mitochondria have important roles in metabolic, regulatory, immunological, developmental and ageing processes. Human mitochondrial DNA (mtDNA) encodes 13 proteins, all of which are membrane protein and essential components of the OXPHOS system. These proteins are synthesized by mitoribosome and then the nascent peptides have been inserted into inner mitochondrial membrane. As we lack basic information on the mechanisms that mitochondria use to synthetize polypeptides, it is poorly understood how the nascent peptide has been inserted into the membrane during the translation. Consequently, understanding the molecular basis of protein synthesis in mitochondria is not only a fundamental question in biology but also of importance in medicine, as mutations in mitochondrial translation machinery cause various progressive or fatal genetic disorders in humans, and disturbed mitochondrial function has shown strong association with aging and the development of neurodegenerative diseases. Mitoribosomes themselves also differ significantly from their prokaryotic and eukaryotic cytosolic counterparts. For example, they display a higher ratio of protein:rRNA content, which is largely attributed to the presence of specific extensions on many ribosomal proteins in addition to their bacterial homology domains. Several novel mitochondrial ribosomal proteins without bacterial counterparts have also recently been described. The recent high-resolution structures of mammalian mitoribosomes have confirmed their evolutionary divergence from other known ribosomes [3-7]. Such structures provide a wealth of novel information on mitoribosome architecture, raising next obvious questions about how these machines function. Of note, The OXPHOS complexes are the product of the nuclear and mitochondrial genomes. This poses a series of topological and temporal steps that must be completed to ensure efficient assembly of the functional enzyme. Many assembly factors have evolved to perform these steps for insertion of protein into the inner mitochondrial membrane, maturation of the polypeptide, incorporation of co-factors and prosthetic groups and to regulate this process. The goal of this project is to understand the mechanisms and regulation of the different steps of how assembly factors coordinate to mitochondrial protein synthesis, focusing on cytochrome c oxidase complex.