Queuine Ameliorates Impaired Mitochondrial Function Caused by Mt-tRNA Variants

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Aug 22

PMID 39175050

Authors

Yan Lin

Jiayin Wang

Xingyu Zhuang

Ying Zhao

Wei Wang

Dongdong Wang

YuYing Zhao

Chuanzhu Yan

Kunqian Ji

Affiliations

Soon will be listed here.

Abstract

Background: Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNA have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNA variants.

Methods: Six patients (from four families) carrying mt-tRNA variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNA variants was evaluated.

Results: The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNA. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNA, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species.

Conclusions: The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNA variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNA and rescue mitochondrial dysfunction caused by mt-tRNA variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNA variants.

References

Lin H, Miyauchi K, Harada T, Okita R, Takeshita E, Komaki H . CO-sensitive tRNA modification associated with human mitochondrial disease. Nat Commun. 2018; 9(1):1875. PMC: 5951830. DOI: 10.1038/s41467-018-04250-4. View

Tuorto F, Legrand C, Cirzi C, Federico G, Liebers R, Muller M . Queuosine-modified tRNAs confer nutritional control of protein translation. EMBO J. 2018; 37(18). PMC: 6138434. DOI: 10.15252/embj.201899777. View

Delaunay S, Pascual G, Feng B, Klann K, Behm M, Hotz-Wagenblatt A . Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature. 2022; 607(7919):593-603. PMC: 9300468. DOI: 10.1038/s41586-022-04898-5. View

Fergus C, Barnes D, Alqasem M, Kelly V . The queuine micronutrient: charting a course from microbe to man. Nutrients. 2015; 7(4):2897-929. PMC: 4425180. DOI: 10.3390/nu7042897. View

Lin Y, Xu X, Wang W, Liu F, Zhao D, Li D . A mitochondrial myopathy-associated tRNA 7453G>A mutation alters tRNA metabolism and mitochondrial function. Mitochondrion. 2020; 57:1-8. DOI: 10.1016/j.mito.2020.11.015. View

Hansen S, Andersen M, Cornett C, Gradinaru R, Grunnet N . A role for taurine in mitochondrial function. J Biomed Sci. 2010; 17 Suppl 1:S23. PMC: 2994382. DOI: 10.1186/1423-0127-17-S1-S23. View

Kulkarni S, Rubio M, Hegedusova E, Ross R, Limbach P, Alfonzo J . Preferential import of queuosine-modified tRNAs into Trypanosoma brucei mitochondrion is critical for organellar protein synthesis. Nucleic Acids Res. 2021; 49(14):8247-8260. PMC: 8373054. DOI: 10.1093/nar/gkab567. View

Qian W, Kumar N, Roginskaya V, Fouquerel E, Opresko P, Shiva S . Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction. Proc Natl Acad Sci U S A. 2019; 116(37):18435-18444. PMC: 6744920. DOI: 10.1073/pnas.1910574116. View

Hung S, Elliott G, Ramkumar T, Burtnyak L, McGrenaghan C, Alkuzweny S . Structural basis of Qng1-mediated salvage of the micronutrient queuine from queuosine-5'-monophosphate as the biological substrate. Nucleic Acids Res. 2023; 51(2):935-951. PMC: 9881137. DOI: 10.1093/nar/gkac1231. View

10.

Birch-Machin M, Turnbull D . Assaying mitochondrial respiratory complex activity in mitochondria isolated from human cells and tissues. Methods Cell Biol. 2001; 65:97-117. DOI: 10.1016/s0091-679x(01)65006-4. View

11.

Liu L, Wu J, Lu C, Ma Y, Wang J, Xu J . WTAP-mediated mA modification of lncRNA Snhg1 improves myocardial ischemia-reperfusion injury via miR-361-5p/OPA1-dependent mitochondrial fusion. J Transl Med. 2024; 22(1):499. PMC: 11128115. DOI: 10.1186/s12967-024-05330-4. View

12.

Muller M, Legrand C, Tuorto F, Kelly V, Atlasi Y, Lyko F . Queuine links translational control in eukaryotes to a micronutrient from bacteria. Nucleic Acids Res. 2019; 47(7):3711-3727. PMC: 6468285. DOI: 10.1093/nar/gkz063. View

13.

Rakovich T, Boland C, Bernstein I, Chikwana V, Iwata-Reuyl D, Kelly V . Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation. J Biol Chem. 2011; 286(22):19354-63. PMC: 3103313. DOI: 10.1074/jbc.M111.219576. View

14.

Gorman G, Schaefer A, Ng Y, Gomez N, Blakely E, Alston C . Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol. 2015; 77(5):753-9. PMC: 4737121. DOI: 10.1002/ana.24362. View

15.

Lin S, Liu Q, Lelyveld V, Choe J, Szostak J, Gregory R . Mettl1/Wdr4-Mediated mG tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation. Mol Cell. 2018; 71(2):244-255.e5. PMC: 6086580. DOI: 10.1016/j.molcel.2018.06.001. View

16.

Bai R, Balog A, Kiesler P, Arjona D, Cui H . Comment on the criteria for interpretation of mitochondrial tRNA variants. Genet Med. 2020; 22(8):1418-1419. DOI: 10.1038/s41436-020-0804-7. View

17.

Chen C, Guan M . Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations. J Biomed Sci. 2023; 30(1):82. PMC: 10515435. DOI: 10.1186/s12929-023-00967-7. View

18.

Ivanov P, Emara M, Villen J, Gygi S, Anderson P . Angiogenin-induced tRNA fragments inhibit translation initiation. Mol Cell. 2011; 43(4):613-23. PMC: 3160621. DOI: 10.1016/j.molcel.2011.06.022. View

19.

Ji K, Lin Y, Xu X, Wang W, Wang D, Zhang C . MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNA and remarkable mitochondrial dysfunction. J Med Genet. 2020; 59(1):79-87. DOI: 10.1136/jmedgenet-2020-107323. View

20.

Ivanov P, ODay E, Emara M, Wagner G, Lieberman J, Anderson P . G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. Proc Natl Acad Sci U S A. 2014; 111(51):18201-6. PMC: 4280610. DOI: 10.1073/pnas.1407361111. View