bims-mitran 2024-05-26 papers

bims-mitran

Biomed News

on Mitochondrial translation

Issue of 2024–05–26
eight papers selected by
Andreas Kohler, Umeå University

Decoding the Enigma: Translation Termination in Human Mitochondria.
Coordinating mitochondrial translation with assembly of the OXPHOS complexes.
Illuminating mitochondrial translation through mouse models.
Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk.
RNA degradation in human mitochondria: the journey is not finished.
Central dogma rates in human mitochondria.
The molecular machinery for maturation of primary mtDNA transcripts.
Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.

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
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
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
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): 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): 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): 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
Hum Mol Genet. 2024 May 22. 33(R1): R3-R11

Origins of tissue and cell-type specificity in mitochondrial DNA (mtDNA) disease.

Stephen P Burr, Patrick F Chinnery.

  Mutations of mitochondrial (mt)DNA are a major cause of morbidity and mortality in humans, accounting for approximately two thirds of diagnosed mitochondrial disease. However, despite significant advances in technology since the discovery of the first disease-causing mtDNA mutations in 1988, the comprehensive diagnosis and treatment of mtDNA disease remains challenging. This is partly due to the highly variable clinical presentation linked to tissue-specific vulnerability that determines which organs are affected. Organ involvement can vary between different mtDNA mutations, and also between patients carrying the same disease-causing variant. The clinical features frequently overlap with other non-mitochondrial diseases, both rare and common, adding to the diagnostic challenge. Building on previous findings, recent technological advances have cast further light on the mechanisms which underpin the organ vulnerability in mtDNA diseases, but our understanding is far from complete. In this review we explore the origins, current knowledge, and future directions of research in this area.

Keywords:  heteroplasmy; mitochondria; mtDNA; single cell

DOI:  https://doi.org/10.1093/hmg/ddae059