bims-tricox 2024-05-26 papers

bims-tricox

Biomed News

on Translation, ribosomes and COX

Issue of 2024–05–26
ten papers selected by
Yash Verma, University of Zurich

Decoding the Enigma: Translation Termination in Human Mitochondria.
Eukaryotic Ribosome Assembly.
Conserved quality control mechanisms of mitochondrial protein import.
Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.
Illuminating mitochondrial translation through mouse models.
Central dogma rates in human mitochondria.
RNA degradation in human mitochondria: the journey is not finished.
The molecular machinery for maturation of primary mtDNA transcripts.
Mitochondrial Chaperone Code: Just Warming Up.

Hum Mol Genet. 2024 May 22. 33(R1): R42-R46

Decoding the Enigma: Translation Termination in Human Mitochondria.

Annika Krüger, Daria Kovalchuk, Dmitrii Shiriaev, Joanna Rorbach.

  Mitochondrial translation is a complex process responsible for the synthesis of essential proteins involved in oxidative phosphorylation, a fundamental pathway for cellular energy production. Central to this process is the termination phase, where dedicated factors play a pivotal role in ensuring accurate and timely protein production. This review provides a comprehensive overview of the current understanding of translation termination in human mitochondria, emphasizing structural features and molecular functions of two mitochondrial termination factors mtRF1 and mtRF1a.

Keywords:  Mitochondrial translation; mitochondrial translation termination factors; mitoribosomes

DOI:  https://doi.org/10.1093/hmg/ddae032
Annu Rev Biochem. 2024 May 20.

Eukaryotic Ribosome Assembly.

Arnaud Vanden Broeck, Sebastian Klinge.

During the last ten years, developments in cryo-electron microscopy have transformed our understanding of eukaryotic ribosome assembly. As a result, the field has advanced from a list of the vast array of ribosome assembly factors toward an emerging molecular movie in which individual frames are represented by structures of stable ribosome assembly intermediates with complementary biochemical and genetic data. In this review, we discuss the mechanisms driving the assembly of yeast and human small and large ribosomal subunits. A particular emphasis is placed on the most recent findings that illustrate key concepts of ribosome assembly, such as folding of preribosomal RNA, the enforced chronology of assembly, enzyme-mediated irreversible transitions, and proofreading of preribosomal particles.

DOI: https://doi.org/10.1146/annurev-biochem-030222-113611
J Inherit Metab Dis. 2024 May 24.

Conserved quality control mechanisms of mitochondrial protein import.

Lion Borgert, Thomas Becker, Fabian den Brave.

  Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900-1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.

Keywords:  TOM complex; mitoTAD; mitochondria; protein quality control; protein sorting

DOI:  https://doi.org/10.1002/jimd.12756
Hum Mol Genet. 2024 May 22. 33(R1): R47-R52

Coordinating mitochondrial translation with assembly of the OXPHOS complexes.

Laura S Kremer, Peter Rehling.

  The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS machinery is still under dual genetic control where most OXPHOS subunits are encoded by the nuclear DNA and imported into mitochondria, while a small subset is encoded on the mitochondrion's own genome, the mitochondrial DNA (mtDNA). The nuclear and mtDNA encoded subunits must be expressed and assembled in a highly orchestrated fashion to form a functional OXPHOS system and meanwhile prevent the generation of any harmful assembly intermediates. While several mechanisms have evolved in eukaryotes to achieve such a coordinated expression, this review will focus on how the translation of mtDNA encoded OXPHOS subunits is tailored to OXPHOS assembly.

Keywords:  Coordination of translation and assembly; Gene expression; Mitochondria; OXPHOS assembly; Oxidative phosphorylation (OXPHOS); Translation

DOI:  https://doi.org/10.1093/hmg/ddae025
Nat Commun. 2024 May 20. 15(1): 4272

Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.

Vivek Singh, Yuzuru Itoh, Samuel Del'Olio, Asem Hassan, Andreas Naschberger, Rasmus Kock Flygaard, Yuko Nobe, Keiichi Izumikawa, Shintaro Aibara, Juni Andréll, Paul C Whitford, Antoni Barrientos, Masato Taoka, Alexey Amunts.

The mitoribosome translates mitochondrial mRNAs and regulates energy conversion that is a signature of aerobic life forms. We present a 2.2 Å resolution structure of human mitoribosome together with validated mitoribosomal RNA (rRNA) modifications, including aminoacylated CP-tRNAVal. The structure shows how mitoribosomal proteins stabilise binding of mRNA and tRNA helping to align it in the decoding center, whereas the GDP-bound mS29 stabilizes intersubunit communication. Comparison between different states, with respect to tRNA position, allowed us to characterize a non-canonical L1 stalk, and molecular dynamics simulations revealed how it facilitates tRNA transitions in a way that does not require interactions with rRNA. We also report functionally important polyamines that are depleted when cells are subjected to an antibiotic treatment. The structural, biochemical, and computational data illuminate the principal functional components of the translation mechanism in mitochondria and provide a description of the structure and function of the human mitoribosome.

DOI: https://doi.org/10.1038/s41467-024-48163-x
Hum Mol Genet. 2024 May 22. 33(R1): R61-R79

Illuminating mitochondrial translation through mouse models.

Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska.

  Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.

Keywords:  animal models; gene expression; mitochondria; protein synthesis

DOI:  https://doi.org/10.1093/hmg/ddae020
Hum Mol Genet. 2024 May 22. 33(R1): R34-R41

Central dogma rates in human mitochondria.

Erik McShane, L Stirling Churchman.

  In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.

Keywords:  gene regulation; mitochondrial DNA; mitonuclear balance; oxidative phosphorylation

DOI:  https://doi.org/10.1093/hmg/ddae036
Hum Mol Genet. 2024 May 22. 33(R1): R26-R33

RNA degradation in human mitochondria: the journey is not finished.

Giulia Santonoceto, Aneta Jurkiewicz, Roman J Szczesny.

  Mitochondria are vital organelles present in almost all eukaryotic cells. Although most of the mitochondrial proteins are nuclear-encoded, mitochondria contain their own genome, whose proper expression is necessary for mitochondrial function. Transcription of the human mitochondrial genome results in the synthesis of long polycistronic transcripts that are subsequently processed by endonucleases to release individual RNA molecules, including precursors of sense protein-encoding mRNA (mt-mRNA) and a vast amount of antisense noncoding RNAs. Because of mitochondrial DNA (mtDNA) organization, the regulation of individual gene expression at the transcriptional level is limited. Although transcription of most protein-coding mitochondrial genes occurs with the same frequency, steady-state levels of mature transcripts are different. Therefore, post-transcriptional processes are important for regulating mt-mRNA levels. The mitochondrial degradosome is a complex composed of the RNA helicase SUV3 (also known as SUPV3L1) and polynucleotide phosphorylase (PNPase, PNPT1). It is the best-characterized RNA-degrading machinery in human mitochondria, which is primarily responsible for the decay of mitochondrial antisense RNA. The mechanism of mitochondrial sense RNA decay is less understood. This review aims to provide a general picture of mitochondrial genome expression, with a particular focus on mitochondrial RNA (mtRNA) degradation.

Keywords:  mitochondrial RNA decay; mitochondrial RNA surveillance; mitochondrial gene expression; polyadenylation

DOI:  https://doi.org/10.1093/hmg/ddae043
Hum Mol Genet. 2024 May 22. 33(R1): R19-R25

The molecular machinery for maturation of primary mtDNA transcripts.

Ana Vučković, Christoph Freyer, Anna Wredenberg, Hauke S Hillen.

  Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.

Keywords:  Mitochondria; Mitochondriopathy; RNA; RNA Processing

DOI:  https://doi.org/10.1093/hmg/ddae023
Cell Stress Chaperones. 2024 May 17. pii: S1355-8145(24)00074-9. [Epub ahead of print]

Mitochondrial Chaperone Code: Just Warming Up.

R Felipe Perez, Gianna Mochi, Ariba Khan, Mark Woodford.

  More than 99% of the mitochondrial proteome is encoded by the nucleus and requires refolding following import. Therefore, mitochondrial proteins require the coordinated action of molecular chaperones for their folding and activation. Several heat shock protein (Hsp) molecular chaperones, including members of the Hsp27, Hsp40/70, and Hsp90 families, as well as the chaperonin complex Hsp60/10 have an established role in mitochondrial protein import and folding. The 'Chaperone Code' describes the regulation of chaperone activity by dynamic post-translational modifications; however, little is known about post-translational regulation of mitochondrial chaperones. Dissecting the regulation of chaperone function is essential for understanding their differential regulation in pathogenic conditions and the potential development of efficacious therapeutic strategies. Here, we summarize the recent literature on post-translational regulation of mitochondrial chaperones, the consequences for mitochondrial function, and potential implications for disease.

Keywords:  chaperones; heat shock proteins; metabolism; mitochondria; post-translational modification

DOI:  https://doi.org/10.1016/j.cstres.2024.05.002