bims-mitran 2025-11-09 papers

Issue of 2025–11–09
five papers selected by
Andreas Kohler, Umeå University

Nat Genet. 2025 Nov 03.

Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

DOI: https://doi.org/10.1038/s41588-025-02374-0

Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.

Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.

Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.

Keywords: aging; metabolism; mitochondria; mitoribosome; translation activity

DOI: https://doi.org/10.1016/j.molcel.2025.10.012

Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):

Proteolytic cleavage activates the mitochondrial isoform of TOP3A.

Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.

The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.

DOI: https://doi.org/10.1093/nar/gkaf1140

J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.

Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.

Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.

Keywords: Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone

DOI: https://doi.org/10.1093/jb/mvaf062