bims-mitran Biomed News
on Mitochondrial Translation
Issue of 2021‒08‒08
twelve papers selected by
Andreas Aufschnaiter
Stockholm University

  1. Mitochondrion. 2021 Jul 30. pii: S1567-7249(21)00101-X. [Epub ahead of print]
      As ancient bacterial endosymbionts of eukaryotic cells, mitochondria have retained their own circular DNA as well as protein translation system including mitochondrial ribosomes (mitoribosomes). In recent years, methodological advancements in cryoelectron microscopy and mass spectrometry have revealed the extent of the evolutionary divergence of mitoribosomes from their bacterial ancestors and their adaptation to the synthesis of 13 mitochondrial DNA encoded oxidative phosphorylation complex subunits. In addition to the structural data, the first assembly pathway maps of mitoribosomes have started to emerge and concomitantly also the assembly factors involved in this process to achieve fully translational competent particles. These transiently associated factors assist in the intricate assembly process of mitoribosomes by enhancing protein incorporation, ribosomal RNA folding and modification, and by blocking premature or non-native protein binding, for example. This review focuses on summarizing the current understanding of the known mammalian mitoribosome assembly factors and discussing their possible roles in the assembly of small or large mitoribosomal subunits.
    Keywords:  mitochondrial translation; mitoribosome assembly factors; mitoribosome biogenesis
  2. Front Genet. 2021 ;12 673951
      Mitochondrial DNA (mtDNA) encodes vital proteins and RNAs for the normal functioning of the mitochondria. Mutations in mtDNA leading to mitochondrial dysfunction are relevant to a large spectrum of diseases, including fertility disorders. Since mtDNA undergoes rather complex processes during gametogenesis and fertilization, clarification of the changes and functions of mtDNA and its essential impact on gamete quality and fertility during this process is of great significance. Thanks to the emergence and rapid development of gene editing technology, breakthroughs have been made in mitochondrial genome editing (MGE), offering great potential for the treatment of mtDNA-related diseases. In this review, we summarize the features of mitochondria and their unique genome, emphasizing their inheritance patterns; illustrate the role of mtDNA in gametogenesis and fertilization; and discuss potential therapies based on MGE as well as the outlook in this field.
    Keywords:  gene therapy; human infertility; mitochondria DNA mutation; mitochondrial DNA; mitochondrial genome editing
  3. Int J Mol Sci. 2021 Jul 27. pii: 7999. [Epub ahead of print]22(15):
      Mitochondria, often referred to as the powerhouses of cells, are vital organelles that are present in almost all eukaryotic organisms, including humans. They are the key energy suppliers as the site of adenosine triphosphate production, and are involved in apoptosis, calcium homeostasis, and regulation of the innate immune response. Abnormalities occurring in mitochondria, such as mitochondrial DNA (mtDNA) mutations and disturbances at any stage of mitochondrial RNA (mtRNA) processing and translation, usually lead to severe mitochondrial diseases. A fundamental line of investigation is to understand the processes that occur in these organelles and their physiological consequences. Despite substantial progress that has been made in the field of mtRNA processing and its regulation, many unknowns and controversies remain. The present review discusses the current state of knowledge of RNA processing in human mitochondria and sheds some light on the unresolved issues.
    Keywords:  RNA decay; RNA modifications; RNA processing; mitochondria; mitochondrial genome; mitochondrial transcription
  4. Genes (Basel). 2021 Jul 01. pii: 1031. [Epub ahead of print]12(7):
      In human mitochondria, mtDNA encodes for only 13 proteins, all components of the OXPHOS system. The rest of the mitochondrial components, which make up approximately 99% of its proteome, are encoded in the nuclear genome, synthesized in cytosolic ribosomes and imported into mitochondria. Different import machineries translocate mitochondrial precursors, depending on their nature and the final destination inside the organelle. The proper and coordinated function of these molecular pathways is critical for mitochondrial homeostasis. Here, we will review molecular details about these pathways, which components have been linked to human disease and future perspectives on the field to expand the genetic landscape of mitochondrial diseases.
    Keywords:  disease; mitochondria; protein import
  5. Front Mol Biosci. 2021 ;8 716885
      Mitochondria are energy producing organelles of the eukaryotic cell, involved in the synthesis of key metabolites, calcium homeostasis and apoptosis. Protein biosynthesis in these organelles is a relic of its endosymbiotic origin. While mitochondrial translational factors have homologues among prokaryotes, they possess a number of unique traits. Remarkably as many as four mammalian mitochondrial proteins possess a clear similarity with translation termination factors. The review focuses on the ICT1, which combines several functions. It is a non-canonical termination factor for protein biosynthesis, a rescue factor for stalled mitochondrial ribosomes, a structural protein and a regulator of proliferation, cell cycle, and apoptosis. Such a diversity of roles demonstrates the high functionality of mitochondrial translation associated proteins and their relationship with numerous processes occurring in a living cell.
    Keywords:  apoptosis; cell cycle; mitochondria; proliferation; regulation; ribosome, signaling; termination; translation
  6. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00891-3. [Epub ahead of print]36(5): 109468
      Reversible monoubiquitination of small subunit ribosomal proteins RPS2/uS5 and RPS3/uS3 has been noted to occur on ribosomes involved in ZNF598-dependent mRNA surveillance. Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome-associated quality control. Here, we identify and characterize the RPS2- and RPS3-specific E3 ligase Really Interesting New Gene (RING) finger protein 10 (RNF10) and its role in translation. Overexpression of RNF10 increases 40S ribosomal subunit degradation similarly to the knockout of USP10. Although a substantial fraction of RNF10-mediated RPS2 and RPS3 monoubiquitination results from ZNF598-dependent sensing of collided ribosomes, ZNF598-independent impairment of translation initiation and elongation also contributes to RPS2 and RPS3 monoubiquitination. RNF10 photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) identifies crosslinked mRNAs, tRNAs, and 18S rRNAs, indicating recruitment of RNF10 to ribosomes stalled in translation. These impeded ribosomes are tagged by ubiquitin at their 40S subunit for subsequent programmed degradation unless rescued by USP10.
    Keywords:  E3 ubiquitin ligase; RNA-binding protein; mRNA surveillance; regulatory protein ubiquitination; ribosome collision; ribosome-associated quality control; translation
  7. Nucleic Acids Res. 2021 Aug 06. pii: gkab667. [Epub ahead of print]
      DDX3 is a multifaceted RNA helicase of the DEAD-box family that plays central roles in all aspects of RNA metabolism including translation initiation. Here, we provide evidence that the Leishmania DDX3 ortholog functions in post-initiation steps of translation. We show that genetic depletion of DDX3 slows down ribosome movement resulting in elongation-stalled ribosomes, impaired translation elongation and decreased de novo protein synthesis. We also demonstrate that the essential ribosome recycling factor Rli1/ABCE1 and termination factors eRF3 and GTPBP1 are less recruited to ribosomes upon DDX3 loss, suggesting that arrested ribosomes may be inefficiently dissociated and recycled. Furthermore, we show that prolonged ribosome stalling triggers co-translational ubiquitination of nascent polypeptide chains and a higher recruitment of E3 ubiquitin ligases and proteasome components to ribosomes of DDX3 knockout cells, which further supports that ribosomes are not elongating optimally. Impaired elongation of translating ribosomes also results in the accumulation of cytoplasmic protein aggregates, which implies that defects in translation overwhelm the normal quality controls. The partial recovery of translation by overexpressing Hsp70 supports this possibility. Collectively, these results suggest an important novel contribution of DDX3 to optimal elongation of translating ribosomes by preventing prolonged translation stalls and stimulating recycling of arrested ribosomes.
  8. Nat Commun. 2021 08 04. 12(1): 4696
      Productive ribosomal RNA (rRNA) compaction during ribosome assembly necessitates establishing correct tertiary contacts between distant secondary structure elements. Here, we quantify the response of the yeast proteome to low temperature (LT), a condition where aberrant mis-paired RNA folding intermediates accumulate. We show that, at LT, yeast cells globally boost production of their ribosome assembly machinery. We find that the LT-induced assembly factor, Puf6, binds to the nascent catalytic RNA-rich subunit interface within the 60S pre-ribosome, at a site that eventually loads the nuclear export apparatus. Ensemble Förster resonance energy transfer studies show that Puf6 mimics the role of Mg2+ to usher a unique long-range tertiary contact to compact rRNA. At LT, puf6 mutants accumulate 60S pre-ribosomes in the nucleus, thus unveiling Puf6-mediated rRNA compaction as a critical temperature-regulated rescue mechanism that counters rRNA misfolding to prime export competence.
  9. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00905-0. [Epub ahead of print]36(5): 109478
      Oxidative stress is a ubiquitous cellular challenge implicated in aging, neurodegeneration, and cancer. By studying pathogenic mutations in the tumor suppressor BRCA2, we identify a general mechanism by which oxidative stress restricts mitochondrial (mt)DNA replication. BRCA2 inactivation induces R-loop accumulation in the mtDNA regulatory region and diminishes mtDNA replication initiation. In BRCA2-deficient cells, intracellular reactive oxygen species (ROS) are elevated, and ROS scavengers suppress the mtDNA defects. Conversely, wild-type cells exposed to oxidative stress by pharmacologic or genetic manipulation phenocopy these defects. Mechanistically, we find that 8-oxoguanine accumulation in mtDNA caused by oxidative stress suffices to impair recruitment of the mitochondrial enzyme RNaseH1 to sites of R-loop accrual, restricting mtDNA replication initiation. Thus, oxidative stress impairs RNaseH1 function to cripple mtDNA maintenance. Our findings highlight a molecular mechanism that links oxidative stress to mitochondrial dysfunction and is elicited by the inactivation of genes implicated in neurodegeneration and cancer.
    Keywords:  BRCA2; PRPF8; R-loops; RNaseH1; SETX; cancer; mitochondrial DNA replication; neurodegeneration; oxidative stress
  10. Nat Commun. 2021 Aug 05. 12(1): 4723
      Translational riboswitches are cis-acting RNA regulators that modulate the expression of genes during translation initiation. Their mechanism is considered as an RNA-only gene-regulatory system inducing a ligand-dependent shift of the population of functional ON- and OFF-states. The interaction of riboswitches with the translation machinery remained unexplored. For the adenine-sensing riboswitch from Vibrio vulnificus we show that ligand binding alone is not sufficient for switching to a translational ON-state but the interaction of the riboswitch with the 30S ribosome is indispensable. Only the synergy of binding of adenine and of 30S ribosome, in particular protein rS1, induces complete opening of the translation initiation region. Our investigation thus unravels the intricate dynamic network involving RNA regulator, ligand inducer and ribosome protein modulator during translation initiation.
  11. Nucleic Acids Res. 2021 Aug 05. pii: gkab652. [Epub ahead of print]
      Translation reinitiation is a gene-specific translational control mechanism. It is characterized by the ability of short upstream ORFs to prevent full ribosomal recycling and allow the post-termination 40S subunit to resume traversing downstream for the next initiation event. It is well known that variable transcript-specific features of various uORFs and their prospective interactions with initiation factors lend them an unequivocal regulatory potential. Here, we investigated the proposed role of the major initiation scaffold protein eIF4G in reinitiation and its prospective interactions with uORF's cis-acting features in yeast. In analogy to the eIF3 complex, we found that eIF4G and eIF4A but not eIF4E (all constituting the eIF4F complex) are preferentially retained on ribosomes elongating and terminating on reinitiation-permissive uORFs. The loss of the eIF4G contact with eIF4A specifically increased this retention and, as a result, increased the efficiency of reinitiation on downstream initiation codons. Combining the eIF4A-binding mutation with that affecting the integrity of the eIF4G1-RNA2-binding domain eliminated this specificity and produced epistatic interaction with a mutation in one specific cis-acting feature. We conclude that similar to humans, eIF4G is retained on ribosomes elongating uORFs to control reinitiation also in yeast.
  12. Nat Rev Cancer. 2021 Aug 02.
      Translational control of mRNAs during gene expression allows cells to promptly and dynamically adapt to a variety of stimuli, including in neoplasia in response to aberrant oncogenic signalling (for example, PI3K-AKT-mTOR, RAS-MAPK and MYC) and microenvironmental stress such as low oxygen and nutrient supply. Such translational rewiring allows rapid, specific changes in the cell proteome that shape specific cancer phenotypes to promote cancer onset, progression and resistance to anticancer therapies. In this Review, we illustrate the plasticity of mRNA translation. We first highlight the diverse mechanisms by which it is regulated, including by translation factors (for example, eukaryotic initiation factor 4F (eIF4F) and eIF2), RNA-binding proteins, tRNAs and ribosomal RNAs that are modulated in response to aberrant intracellular pathways or microenvironmental stress. We then describe how translational control can influence tumour behaviour by impacting on the phenotypic plasticity of cancer cells as well as on components of the tumour microenvironment. Finally, we highlight the role of mRNA translation in the cellular response to anticancer therapies and its promise as a key therapeutic target.