bims-mitran 2023-03-19 papers

Issue of 2023‒03‒19
two papers selected by
Andreas Kohler

Nucleic Acids Res. 2023 Mar 17. pii: gkad139. [Epub ahead of print]

Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases.

Ena Tomoda, Asuteka Nagao, Yuki Shirai, Kana Asano, Takeo Suzuki, Brendan J Battersby, Tsutomu Suzuki.

Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.

DOI: https://doi.org/10.1093/nar/gkad139

Front Genet. 2023 ;14 1130411

Impact of genetically predicted characterization of mitochondrial DNA quantity and quality on osteoarthritis.

Houpu Liu, Bingyue Cai, Ruicheng Gong, Ye Yang, Jing Wang, Dan Zhou, Min Yu, Yingjun Li.

Background: Existing studies have indicated that mitochondrial dysfunction may contribute to osteoarthritis (OA) development. However, the causal association between mitochondrial DNA (mtDNA) characterization and OA has not been extensively explored. Methods: Two-sample Mendelian randomization was performed to calculate the impact of mitochondrial genomic variations on overall OA as well as site-specific OA, with multiple analytical methods inverse variance weighted (IVW), weighted median (WM), MR-Egger and MR-robust adjusted profile score (MR-RAPS). Results: Genetically determined mitochondrial heteroplasmy (MtHz) and mtDNA abundance were not causally associated with overall OA. In site-specific OA analyses, the causal effect of mtDNA abundance on other OA sites, including hip, knee, thumb, hand, and finger, had not been discovered. There was a suggestively protective effect of MtHz on knee OA IVW OR = 0.632, 95% CI: 0.425-0.939, p-value = 0.023. No causal association between MtHz and other different OA phenotypes was found. Conclusion: MtHz shows potential to be a novel therapeutic target and biomarker on knee OA development. However, the variation of mtDNA abundance was measured from leukocyte in blood and the levels of MtHz were from saliva samples rather than cartilage or synovial tissues. Genotyping samples from synovial and cartilage can be a focus to further exploration.

Keywords: knee OA (KOA); mendelian randomization; mitochondrial abundance; mitochondrial heteroplasmy; osteoarthritis

DOI: https://doi.org/10.3389/fgene.2023.1130411