bims-mitran Biomed News
on Mitochondrial translation
Issue of 2025–02–16
six papers selected by
Andreas Kohler, Umeå University
  1. A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
  2. TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA.
  3. Advances in human pre-tRNA maturation : TRMT10C and ELAC2 in focus.
  4. Poldip2 promotes mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance.
  5. Mitochondrial DNA removal is essential for sperm development and activity.
  6. Saccharomyces cerevisiae Dmo2p is required for the stability and maturation of newly translated Cox2p.
  1. Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01494-3. [Epub ahead of print]44(1): 115143
    A microscopy-based screen identifies cellular kinases modulating mitochondrial translation.
    Roya Yousefi, Luis Daniel Cruz-Zaragoza, Anusha Valpadashi, Carina Hansohn, Drishan Dahal, Ricarda Richter-Dennerlein, Silvio Rizzoli, Henning Urlaub, Peter Rehling, David Pacheu-Grau.
      Mitochondrial DNA encodes 13 subunits of the oxidative phosphorylation (OXPHOS) system, which are synthesized inside the organelle and essential for cellular energy supply. How mitochondrial gene expression is regulated and integrated into cellular physiology is little understood. Here, we perform a high-throughput screen combining fluorescent labeling of mitochondrial translation products with small interfering RNA (siRNA)-mediated knockdown to identify cellular kinases regulating translation. As proof of principle, the screen identifies known kinases that affect mitochondrial translation, and it also reveals several kinases not yet linked to this process. Among the latter, we focus on the primarily cytosolic kinase, fructosamine 3 kinase (FN3K), which localizes partially to the mitochondria to support translation. FN3K interacts with the mitochondrial ribosome and modulates its assembly, thereby affecting translation. Overall, our work provides a reliable approach to identify protein functions for mitochondrial gene expression in a high-throughput manner.
    Keywords:  CP: Metabolism; CP: Molecular biology; cellular kinases; click chemistry; mito-FUNCAT; mitochondrial translation; siRNA library
    DOI:  https://doi.org/10.1016/j.celrep.2024.115143
  2. Commun Biol. 2025 Feb 08. 8(1): 202
    TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA.
    Shigeru Matsuda, Masunari Nakayama, Yura Do, Takashi Ishiuchi, Mikako Yagi, Sjoerd Wanrooij, Kazuto Nakada, Fan-Yan Wei, Kenji Ichiyanagi, Hiroyuki Sasaki, Dongchon Kang, Takehiro Yasukawa.
      Transcription of human mitochondrial DNA (mtDNA) begins from specific transcription promoters. In strand-asynchronous mtDNA replication, transcripts from the light-strand promoter serve as primers for leading-strand synthesis at the origin of the H-strand replication (OH). A 7S DNA strand, a presumed aborted replication product, is also synthesized from OH. Transition from RNA synthesis to DNA synthesis at OH is crucial for balancing replication with transcription, yet the mechanism remains unclear. Herein, we examine the role of mitochondrial transcription elongation factor (TEFM) in this process. TEFM knockout results in decreased 7S DNA, strand-asynchronous replication intermediates, and mtDNA copy number, all of which are concordant with downregulation of RNA-to-DNA transition at OH. Conversely, levels of tRNAs encoded near transcription promoters increase, indicating enhanced transcription initiation frequency. Taken together, we propose that, in addition to conferring processivity to the mitochondrial RNA polymerase, TEFM plays a crucial role in maintaining the balance between mitochondrial transcription and replication.
    DOI:  https://doi.org/10.1038/s42003-025-07645-4
  3. J Mol Biol. 2025 Feb 10. pii: S0022-2836(25)00055-5. [Epub ahead of print] 168989
    Advances in human pre-tRNA maturation : TRMT10C and ELAC2 in focus.
    Juhi Sikarwar, Vincent Meynier, Carine Tisné.
      Mitochondrial pre-tRNA maturation is a multi-step process involving the removal of the 5'-leader by PRORP, 3'-trailer processing by ELAC2, 3'-CCA addition by TRNT1, and the incorporation of post-transcriptional modifications. In metazoans, the low structural stability of mitochondrial pre-tRNAs adds significant complexity to these steps, and defects in their maturation have been implicated in various human mitochondrial disorders. In this case, the tRNA methyltransferase complex TRMT10C/SDR5C1 compensates for the pre-tRNA structural alteration to present the pre-tRNA to maturation enzymes. Cryo-electron microscopy structures of human mitochondrial pre-tRNA maturation complexes have provided critical insights into these essential processes. Here we review the current understanding of tRNA maturation within human mitochondria and explore its implications for nuclear pre-tRNA maturation.
    Keywords:  ELAC2; TRMT10C; TRNT1; mitochondria; pre-tRNA maturation; pre-tRNA processing
    DOI:  https://doi.org/10.1016/j.jmb.2025.168989
  4. EMBO J. 2025 Feb 11.
    Poldip2 promotes mtDNA elimination during Drosophila spermatogenesis to ensure maternal inheritance.
    Ziming Wang, Tirawit Meerod, Nuria Cortes-Silva, Ason C-Y Chiang, Ziyan Nie, Ying Di, Peiqiang Mu, Ankit Verma, Adam James Reid, Hansong Ma.
      Maternal inheritance of mitochondrial DNA (mtDNA) is highly conserved in metazoans. While many species eliminate paternal mtDNA during late sperm development to foster maternal inheritance, the regulatory mechanisms governing this process remain elusive. Through a forward genetic screen in Drosophila, we identified 47 mutant lines exhibiting substantial retention of mtDNA in mature sperm. We mapped one line to poldip2, a gene predominantly expressed in the testis. Disruption of poldip2 led to substantial mtDNA retention in mature sperm and subsequent paternal transmission to progeny. Further investigation via imaging, biochemical analyses and ChIP assays revealed that Poldip2 is a mitochondrial matrix protein capable of binding mtDNA. Moreover, we showed that ClpX, the key component of a major mitochondrial protease, interacts with Poldip2 to co-regulate mtDNA elimination in Drosophila spermatids. This study sheds light on the mechanisms underlying mtDNA removal during spermatogenesis and underscores the pivotal role of this process in safeguarding maternal inheritance.
    Keywords:  ClpXP; Paternal Leakage; Paternal mtDNA Elimination; Poldip2; mtDNA Maternal Inheritance
    DOI:  https://doi.org/10.1038/s44318-025-00378-4
  5. EMBO J. 2025 Feb 11.
    Mitochondrial DNA removal is essential for sperm development and activity.
    Zhe Chen, Fan Zhang, Annie Lee, Michaela Yamine, Zong-Heng Wang, Guofeng Zhang, Christian Combs, Hong Xu.
      Active mitochondrial DNA (mtDNA) elimination during spermatogenesis has emerged as a conserved mechanism ensuring the uniparental mitochondrial inheritance in animals. However, given the existence of post-fertilization processes degrading sperm mitochondria, the physiological significance of mtDNA removal during spermatogenesis is not clear. Here we show that mtDNA clearance is indispensable for sperm development and activity. We uncover a previously unappreciated role of Poldip2 as a mitochondrial exonuclease that is specifically expressed in late spermatogenesis and required for sperm mtDNA elimination in Drosophila. Loss of Poldip2 impairs mtDNA clearance in elongated spermatids and impedes the progression of individualization complexes that strip away cytoplasmic materials and organelles. Over time, poldip2 mutant sperm exhibit marked nuclear genome fragmentation, and the flies become completely sterile. Notably, these phenotypes were rescued by expressing a mitochondrially targeted bacterial exonuclease, which ectopically removes mtDNA. Our work illustrates the developmental necessity of mtDNA clearance for effective cytoplasm removal at the end of spermatid morphogenesis, and for preventing potential nuclear-mitochondrial genome imbalance in mature sperm, in which nuclear genome activity is shut down.
    Keywords:   Drosophila spermatogenesis; EndoG; Exonuclease; Male Sterile; Maternal Inheritance
    DOI:  https://doi.org/10.1038/s44318-025-00377-5
  6. FEBS J. 2025 Feb 11.
    Saccharomyces cerevisiae Dmo2p is required for the stability and maturation of newly translated Cox2p.
    Maria Antônia Kfouri Martins Soares, Letícia Veloso Ribeiro Franco, Jhulia Almeida Clarck Chagas, Fernando Gomes, Mário H Barros.
      Based on available platforms detailing the Saccharomyces cerevisiae mitochondrial proteome and other high-throughput studies, we identified the yeast gene DMO2 as having a profile of genetic and physical interactions that indicate a putative role in mitochondrial respiration. Dmo2p is a homologue to human distal membrane-arm assembly complex protein 1 (DMAC1); both proteins have two conserved cysteines in a Cx2C motif. Here, we localised Dmo2p in the mitochondrial inner membrane with the conserved cysteines facing the intermembrane space. The respiratory deficiency of dmo2 mutants at 37°C led to a reduction in cytochrome c oxidase (COX) activity (COX) and in the formation of cytochrome bc1 complex-COX supercomplexes; dmo2 also has a rapid turnover of Cox2p, the second subunit of the COX complex that harbours the binuclear CuA centre. Moreover, Dmo2p co-immunoprecipitates with Cox2p and components required for maturation of the CuA centre, such as Sco1p and Sco2p. Finally, DMO2 overexpression can suppress cox23 respiratory deficiency, a mutant that has impaired mitochondrial copper homeostasis. Mass spectrometry data unveiled the interaction of Dmo2p with different large molecular complexes, including bc1-COX supercomplexes, the TIM23 machinery and the ADP/ATP nucleotide translocator. Overall, our data suggest that Dmo2p is required for Cox2p maturation, potentially by aiding proteins involved in copper transport and incorporation into Cox2p.
    Keywords:  COX assembly; CuA site formation; DMAC1 homologue
    DOI:  https://doi.org/10.1111/febs.70009
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