bims-mitran 2025-02-02 papers

Issue of 2025–02–02
four papers selected by
Andreas Kohler, Umeå University

Nucleic Acids Res. 2025 Jan 24. pii: gkaf021. [Epub ahead of print]53(3):

Selection of initiator tRNA and start codon by mammalian mitochondrial initiation factor 3 in leaderless mRNA translation.

Muhoon Lee, Taisei Wakigawa, Qimin Jia, Chang Liu, Ruiyuan Huang, Shuai Huang, Asuteka Nagao, Tsutomu Suzuki, Kozo Tomita, Shintaro Iwasaki, Nono Takeuchi-Tomita.

The mammalian mitochondrial protein synthesis system produces 13 essential subunits of oxidative phosphorylation (OXPHOS) complexes. Translation initiation in mammalian mitochondria is characterized by the use of leaderless messenger RNAs (mRNAs) and non-AUG start codons, where the proofreading function of IF-3mt still remains elusive. Here, we developed a reconstituted mammalian mitochondrial translation system using in vitro transcribed and native mitochondrial transfer RNAs (tRNAs) to investigate IF-3mt's proofreading function. Similar to bacterial IF-3, IF-3mt permits an initiator tRNA to participate in initiation by discriminating the three G-C pairs in its anticodon stem, and by the cognate interactions of its anticodon with the AUG start codon. As a result, IF-3mt promotes the accurate initiation of leaderless mRNAs. Nevertheless, IF-3mt can also facilitate initiation from the non-AUG(AUA) start codon through its unique N- and C-terminal extensions, in concert with the 5-methylcytidine (m5C) or 5-formylcytidine (f5C) modification at the anticodon wobble position of mt-tRNAMet. This is partly because the IF-3mt-specific N- and C-terminal extensions and the KKGK-motif favor leaderless mRNA initiation and relax non-AUG start codon discrimination. Analyses of IF-3mt-depleted human cells revealed that IF-3mt indeed participates in translating the open reading frames (ORFs) of leaderless mRNAs, as well as the internal ORFs of dicistronic mRNAs.

DOI: https://doi.org/10.1093/nar/gkaf021

J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):

FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.

Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.

Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.

DOI: https://doi.org/10.1083/jcb.202311082

Medicina (Kaunas). 2025 Jan 09. pii: 96. [Epub ahead of print]61(1):

Mitochondrial Ribosomal Proteins and Cancer.

Huiyi Wu, Xiaowei Zhu, Huilin Zhou, Min Sha, Jun Ye, Hong Yu.

Mitochondria play key roles in maintaining cell life and cell function, and their dysfunction can lead to cell damage. Mitochondrial ribosomal proteins (MRPs) are encoded by nuclear genes and are assembled within the mitochondria. MRPs are pivotal components of the mitochondrial ribosomes, which are responsible for translating 13 mitochondrial DNA-encoded proteins essential for the mitochondrial respiratory chain. Recent studies have underscored the importance of MRPs in cancer biology, revealing their altered expression patterns in various types of cancer and their potential as both prognostic biomarkers and therapeutic targets. Herein, we review the current knowledge regarding the multiple functions of MRPs in maintaining the structure of the mitochondrial ribosome and apoptosis, their implications for cancer susceptibility and progression, and the innovative strategies being developed to target MRPs and mitoribosome biogenesis in cancer therapy. This comprehensive overview aims to provide insights into the role of MRPs in cancer biology and highlight promising strategies for future precision oncology.

Keywords: apoptosis; biomarker; mitochondrial dysfunction; mitoribosome; precision oncology

DOI: https://doi.org/10.3390/medicina61010096

Cell Biosci. 2025 Jan 24. 15(1): 9

Mitochondrial base editing: from principle, optimization to application.

Jinling Tang, Kunzhao Du.

In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddAtox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.

Keywords: DdCBEs; Genetic engineering; Mitochondrial DNA; TALENs; mtDNA base editing

DOI: https://doi.org/10.1186/s13578-025-01351-8