bims-mitran 2023-05-21 papers

Issue of 2023–05–21
five papers selected by
Andreas Kohler, University of Graz

Nucleic Acids Res. 2023 May 19. pii: gkad422. [Epub ahead of print]

Miniature RNAs are embedded in an exceptionally protein-rich mitoribosome via an elaborate assembly pathway.

Matus Valach, Corinna Benz, Lisbeth C Aguilar, Ondřej Gahura, Drahomíra Faktorová, Alena Zíková, Marlene Oeffinger, Gertraud Burger, Michael W Gray, Julius Lukeš.

The mitochondrial ribosome (mitoribosome) has diverged drastically from its evolutionary progenitor, the bacterial ribosome. Structural and compositional diversity is particularly striking in the phylum Euglenozoa, with an extraordinary protein gain in the mitoribosome of kinetoplastid protists. Here we report an even more complex mitoribosome in diplonemids, the sister-group of kinetoplastids. Affinity pulldown of mitoribosomal complexes from Diplonema papillatum, the diplonemid type species, demonstrates that they have a mass of > 5 MDa, contain as many as 130 integral proteins, and exhibit a protein-to-RNA ratio of 11:1. This unusual composition reflects unprecedented structural reduction of ribosomal RNAs, increased size of canonical mitoribosomal proteins, and accretion of three dozen lineage-specific components. In addition, we identified >50 candidate assembly factors, around half of which contribute to early mitoribosome maturation steps. Because little is known about early assembly stages even in model organisms, our investigation of the diplonemid mitoribosome illuminates this process. Together, our results provide a foundation for understanding how runaway evolutionary divergence shapes both biogenesis and function of a complex molecular machine.

DOI: https://doi.org/10.1093/nar/gkad422

Nat Struct Mol Biol. 2023 May 18.

Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity.

Joon Park, Geoffrey K Herrmann, Patrick G Mitchell, Michael B Sherman, Y Whitney Yin.

Accurate replication of mitochondrial DNA (mtDNA) by DNA polymerase γ (Polγ) is essential for maintaining cellular energy supplies, metabolism, and cell cycle control. To illustrate the structural mechanism for Polγ coordinating polymerase (pol) and exonuclease (exo) activities to ensure rapid and accurate DNA synthesis, we determined four cryo-EM structures of Polγ captured after accurate or erroneous incorporation to a resolution of 2.4-3.0 Å. The structures show that Polγ employs a dual-checkpoint mechanism to sense nucleotide misincorporation and initiate proofreading. The transition from replication to error editing is accompanied by increased dynamics in both DNA and enzyme, in which the polymerase relaxes its processivity and the primer-template DNA unwinds, rotates, and backtracks to shuttle the mismatch-containing primer terminus 32 Å to the exo site for editing. Our structural and functional studies also provide a foundation for analyses of Polγ mutation-induced human diseases and aging.

DOI: https://doi.org/10.1038/s41594-023-00980-2

Cell. 2023 May 11. pii: S0092-8674(23)00422-1. [Epub ahead of print]

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Keywords: CHK1; chemical proteomics; chemoresistance; mitochondrial translation; nuclear ROS; nucleus-to-mitochondria signaling

DOI: https://doi.org/10.1016/j.cell.2023.04.026

mSystems. 2023 May 18. e0100222

Metatranscriptomic analysis uncovers prevalent viral ORFs compatible with mitochondrial translation.

Adam Begeman, Artem Babaian, Samantha C Lewis.

RNA viruses are ubiquitous components of the global virosphere, yet relatively little is known about their genetic diversity or the cellular mechanisms by which they exploit the biology of their diverse eukaryotic hosts. A hallmark of (+)ssRNA viruses is the ability to remodel host endomembranes for their own replication. However, the subcellular interplay between RNA viruses and host organelles that harbor gene expression systems, such as mitochondria, is complex and poorly understood. Here we report the discovery of 763 new virus sequences belonging to the family Mitoviridae by metatranscriptomic analysis, the identification of previously uncharacterized mitovirus clades, and a putative new viral class. With this expanded understanding of the diversity of mitovirus and encoded RNA-dependent RNA polymerases, we annotate mitovirus-specific protein motifs and identify hallmarks of mitochondrial translation, including mitochondrion-specific codons. This study expands the known diversity of mitochondrial viruses, and provides additional evidence that they co-opt mitochondrial biology for their survival.IMPORTANCEMetatranscriptomic studies have rapidly expanded the cadre of known RNA viruses, yet our understanding of how these viruses navigate the cytoplasmic milieu of their hosts to survive remains poorly characterized. In this study, we identify and assemble 763 new viral sequences belonging to the Mitoviridae, a family of (+)ssRNA viruses thought to interact with and remodel host host mitochondria. We exploit this genetic diversity to identify new clades of Mitoviridae, annotate clade-specific sequence motifs that distinguish the mitoviral RNA-dependent RNA polymerase, and reveal patterns of RdRp codon usage consistent with translation on host cell mitoribosomes. These results serve as a foundation for understanding how mitoviruses co-opt mitochondrial biology for their proliferation.

Keywords: RNA virus; metagenomics; mitochondria; mitovirus; translation; virus evolution

DOI: https://doi.org/10.1128/msystems.01002-22

Exp Gerontol. 2023 May 10. pii: S0531-5565(23)00124-9. [Epub ahead of print] 112203

The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration.

Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Christiaan Leeuwenburgh, Cecilia Bucci, Emanuele Marzetti.

Mitochondrial DNA (mtDNA) is as a multi-copy genome existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. Accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and older adults, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.

Keywords: Heteroplasmy; Mitochondrial biogenesis; Mitochondrial diseases; Mitochondrial quality; mtDNA deletions; mtDNA mutations

DOI: https://doi.org/10.1016/j.exger.2023.112203