bims-mimuhe 2026-08-16 papers

Issue of 2026–08–16
four papers selected by
Ishika Gupta

Hum Mutat. 2026 ;2026 6788682

Mitochondrial tRNASer(AGY) 12234A > G Mutation May Contribute to the Clinical Expression of Hypertrophic Cardiomyopathy-Associated tRNAIle 4263A > G Mutation.

Mengting Liu, Qinxian Guo, Shunrong Zhang, Daojun Yu, Yu Ding.

Mutations in mitochondrial tRNA (mt-tRNA) are found to be associated with hypertrophic cardiomyopathy (HCM), but their molecular mechanisms remain largely undetermined. In this study, we investigated the contribution of a novel HCM-related mt-tRNASer(AGY) 12234A > G mutation to the phenotypic expression of the mt-tRNAIle 4263A > G mutation in two genetically unrelated Han Chinese pedigrees. Strikingly, the penetrance and expressivity of one pedigree (HCM2) with both m.4263A > G and m.12234A > G mutations are much higher than another pedigree (HCM1) with only m.4263A > G mutation. By molecular level, the homoplasmic m.4263A > G mutation is located at the processing site for the tRNAIle 5 '-end precursor, disrupting a conserved Watson-Crick base pairing (1A-69T) which is believed to cause mitochondrial dysfunction. Moreover, the heteroplasmic m.12234A > G mutation occurs at an extremely conserved nucleotide in the anticodon stem of tRNASer(AGY), a position which is critical for tRNA structure and function. Using trans-mitochondrial cell models, we demonstrated that cybrids with both mt-tRNA mutations exhibited more severe mitochondrial dysfunctions than cybrids with only the m.4263A > G mutation. Furthermore, a marked decrease in mt-RNA transcripts was observed in cells harboring both m.4263A > G and m.12234A > G mutations. Taken together, our study indicated that the m.12234A > G mutation acted in synergy with the m.4263A > G mutation, triggering mitochondrial dysfunctions and contributing to a high penetrance of HCM in a pedigree harboring both mtDNA mutations.

Keywords: hypertrophic cardiomyopathy; m.12234A > G; m.4263A > G; mitochondrial tRNA mutations; synergy

DOI: https://doi.org/10.1155/humu/6788682

G3 (Bethesda). 2026 Aug 12. pii: jkag216. [Epub ahead of print]

Mistranslation protects against lifespan reduction due to mating in Drosophila melanogaster females.

Luana Branco, William Yeung, Joshua R Isaacson, Amanda J Moehring.

Accurate translation of genes into proteins is critical to organism fitness, and errors in this process are usually detrimental and cause proteotoxic stress. Mistranslation occurs when the amino acid that is incorporated into the nascent polypeptide chain does not match what is dictated by the genetic code. Valine-to-serine (V→S) and threonine-to-serine (T→S) mistranslating models of the fruit fly Drosophila melanogaster have demonstrated a surprising, sex-specific increase in virgin female longevity. We predict that the added stressor of reproduction would eliminate this mistranslation-induced lifespan increase since females prioritize reproductive tissues over somatic tissues, and proteotoxic stress would therefore lead to higher protein damage and cell death in the soma of mated females. We measured the impact of reproduction on V→S and T→S mistranslating D. melanogaster by measuring longevity, egg laying, and fecundity. Counter to our prediction, both V→S and T→S mistranslation led to a sex-specific increase in mated female longevity compared to non-mistranslating controls. Additionally, the risk of death decreased for mated females with mistranslation, beyond the pure additive benefits of mistranslation alone. These effects could not be explained by reduced egg laying or fertilization rates in mistranslating females. Thus, we find that the added proteotoxic stress caused by mistranslation does not exacerbate the detrimental effects of reproduction and instead can ameliorate lifespan decreases due to female reproduction.

Keywords: Drosophila melanogaster ; Mistranslation; ageing; fertility; reproduction; tRNA

DOI: https://doi.org/10.1093/g3journal/jkag216

Cancer Res Commun. 2026 Aug 11.

Mitochondrial tRNA-derived fragments as candidate metastasis-modifying RNA.

Katy L Swancutt, R McKinnon Walsh, Sydney Quijano, Emily Schueddig, Devin C Koestler, Adam D Scheid, Tony Vanden Bush, Yi Jing, Isidore Rigoutsos, Danny R Welch.

How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using Mitochondrial-Nuclear eXchange (MNX) mice, we previously showed that mtDNA single nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences. The only mtDNA SNP correlating with these phenotypes resides in the gene encoding mitochondrial tRNA-Arginine (mt-tRNAArg (UCG), mt-TR), suggesting a role for non-protein-coding loci. Here we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TR. Northern blotting revealed distinct tRF that are differentially expressed among mtDNA SNP, between lung and liver, and between sexes. Surprisingly, small RNA sequencing untreated RNA did not detect the same tRF in high abundance. However, demethylating and restoring 5'-OH and 3'-PO4 termini allowed detection of sequences consistent with the northern blot bands. Enforcing exact matching to the mitochondrial genome and normalizing to their parental molecule revealed putative tRF sequences with shared cleavage sites. Based on connections among mtDNA SNP, the resulting SNP-dependent tRF, and SNP-metastasis correlation, we propose that these tRF may function as metastasis modifiers. These data also expand the functional output of the mitochondrial genome that can contribute to phenotype modification.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0360

Nat Rev Mol Cell Biol. 2026 Aug 14.

Regulation and roles of mammalian mitophagy.

Sascha Martens, Ian G Ganley.

Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.

DOI: https://doi.org/10.1038/s41580-026-01012-9