bims-mitran 2024-01-21 papers

Issue of 2024‒01‒21
four papers selected by
Andreas Kohler, Umeå University

Nat Commun. 2024 Jan 19. 15(1): 611

Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality.

Ason C Y Chiang, Jan Ježek, Peiqiang Mu, Ying Di, Anna Klucnika, Martin Jabůrek, Petr Ježek, Hansong Ma.

Genetic screens have been used extensively to probe interactions between nuclear genes and their impact on phenotypes. Probing interactions between mitochondrial genes and their phenotypic outcome, however, has not been possible due to a lack of tools to map the responsible polymorphisms. Here, using a toolkit we previously established in Drosophila, we isolate over 300 recombinant mitochondrial genomes and map a naturally occurring polymorphism at the cytochrome c oxidase III residue 109 (CoIII109) that fully rescues the lethality and other defects associated with a point mutation in cytochrome c oxidase I (CoIT300I). Through lipidomics profiling, biochemical assays and phenotypic analyses, we show that the CoIII109 polymorphism modulates cardiolipin binding to prevent complex IV instability caused by the CoIT300I mutation. This study demonstrates the feasibility of genetic interaction screens in animal mitochondrial DNA. It unwraps the complex intra-genomic interplays underlying disorders linked to mitochondrial DNA and how they influence disease expression.

DOI: https://doi.org/10.1038/s41467-024-44964-2

Nucleic Acids Res. 2024 Jan 16. pii: gkae013. [Epub ahead of print]

Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression.

Yong Zhang, Jing-Bo Zhou, Yue Yin, En-Duo Wang, Xiao-Long Zhou.

N 6-Threonylcarbamoyladenosine at A37 (t6A37) of ANN-decoding transfer RNAs (tRNAs) is a universal modification whose functions have been well documented in bacteria and lower eukaryotes; however, its role in organellar translation is not completely understood. In this study, we deleted the mitochondrial t6A37-modifying enzyme OSGEPL1 in HEK293T cells. OSGEPL1 is dispensable for cell viability. t6A37 hypomodification selectively stimulated N1-methyladenosine at A9 (m1A9) and N2-methylguanosine at G10 (m2G10) modifications and caused a substantial reduction in the aminoacylation of mitochondrial tRNAThr and tRNALys, resulting in impaired translation efficiency. Multiple types of amino acid misincorporation due to the misreading of near-cognate codons by t6A37-unmodified tRNAs were detected, indicating a triggered translational infidelity. Accordingly, the alterations in mitochondrial structure, function, and the activated mitochondrial unfolded protein response were observed. Mitochondrial function was efficiently restored by wild-type, but not by tRNA-binding-defective OSGEPL1. Lastly, in Osgepl1 deletion mice, disruption to mitochondrial translation was evident but resulted in no observable deficiency under physiological conditions in heart, which displays the highest Osgepl1 expression. Taken together, our data delineate the multifaceted roles of mitochondrial t6A37 modification in translation efficiency and quality control in mitochondria.

DOI: https://doi.org/10.1093/nar/gkae013

Acta Naturae. 2023 Oct-Dec;15(4):15(4): 75-82

Testing a Hypothesis of 12S rRNA Methylation by Putative METTL17 Methyltransferase.

A V Mashkovskaia, S S Mariasina, M V Serebryakova, M P Rubtsova, O A Dontsova, P V Sergiev.

Mitochondrial ribosome assembly is a complex multi-step process involving many additional factors. Ribosome formation differs in various groups of organisms. However, there are universal steps of assembly and conservative factors that have been retained in evolutionarily distant taxa. METTL17, the object of the current study, is one of these conservative factors involved in mitochondrial ribosome assembly. It is present in both bacteria and the mitochondria of eukaryotes, in particular mice and humans. In this study, we tested a hypothesis of putative METTL17 methyltransferase activity. MALDI-TOF mass spectrometry was used to evaluate the methylation of a putative METTL17 target - a 12S rRNA region interacting with METTL17 during mitochondrial ribosome assembly. The investigation of METTL17 and other mitochondrial ribosome assembly factors is of both fundamental and practical significance, because defects in mitochondrial ribosome assembly are often associated with human mitochondrial diseases.

Keywords: MALDI-TOF mass spectrometry; RNA methylation; methyltransferases; mitochondrial ribosome; ribosome assembly factors

DOI: https://doi.org/10.32607/actanaturae.25441

Development. 2024 Jan 12. pii: dev.202165. [Epub ahead of print]

Mitochondrial defects triggered by amg-1 mutation elicit UPRmt and phagocytic clearance during spermatogenesis in C. elegans.

Peng Wang, Lianwan Chen, Ning Wang, Long Miao, Yanmei Zhao.

Mitochondria are the powerhouses of many biological processes. During spermatogenesis, post-transcriptional regulation of mitochondrial gene expression is mediated by nuclear-encoded mitochondrial RNA-binding proteins (mtRBPs). We identified AMG-1 as an mtRBP required for reproductive success in C. elegans. amg-1 mutation led to defects in mitochondrial structure and sperm budding, resulting in mitochondria being discarded into residual bodies (RBs), which ultimately delayed spermatogenesis in the proximal gonad. In addition, mitochondrial defects triggered the gonadal mitochondrial unfolded protein response and phagocytic clearance to ensure spermatogenesis but ultimately failed to rescue hermaphroditic fertility. These findings reveal a previously undiscovered role for AMG-1 in regulating C. elegans spermatogenesis, in which mitochondrial-damaged sperm prevented the transmission of defective mitochondria to mature sperm by budding and phagocytic clearance, which may also exist in the reproductive systems of higher organisms.

Keywords: Caenorhabditis elegans ; Mitochondria; Mitochondrial unfolded protein response; Phagocytic clearance; Sperm

DOI: https://doi.org/10.1242/dev.202165