Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations

Huiying Li; Cheng Ai; Xiaofen Jin; Jing Wang; Jun Yu; Yinlong Gao; Douglas C. Wallace; Min-Xin Guan

doi:10.1016/j.jgg.2026.02.003

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2026 > Accepted Manuscript

PDF( 0 KB)

Optic neuropathy arising from the synergy between YARS2 and mitochondrial COX1 mutations

doi: 10.1016/j.jgg.2026.02.003

Huiying Li^a,b,c,
Cheng Ai^a,b,c,
Xiaofen Jin^c,d,
Jing Wang^c,
Jun Yu^a,b,c,
Yinlong Gao^c,e,
Douglas C. Wallace^f,
Min-Xin Guan^a,b,c

a. Center for Mitochondrial Biomedicine and Department of Ophthalmology, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China;
b. Center for Genetic Medicine, International School of Medicine and International Institute of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China;
c. Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, 310058, China;
d. Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China;
e. Department of Genetics and Metabolic Diseases and Division of Medical Genetics and Genomics, the Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China;
f. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA

Funds:

We are grateful to Dr. Xiangtian Zhou from Wenzhou Medical University, China, for his help in performing electroretinogram recording experiments. This work was supported by the grants from the National Natural Science Foundation of China (U25A20134 to M.X.G and 32500514 to C.A.), Zhejiang Provincial Natural Science Foundation of China (LQN25H120002 to X.J.), and Medical and Health Research Project of Zhejiang (2025KY084 to X.J.).

Received Date: 2025-11-10
Accepted Date: 2026-02-02
Rev Recd Date: 2026-01-29

Available Online: 2026-02-09

Abstract

Abstract

Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy. Here, we investigate the mechanism underlying the interaction between nuclear modifier and mtDNA mutation(s) that manifests optic neuropathy in vivo to develop an effective therapeutic approach for this disease using mouse models bearing LHON-linked Yars2^G186V or COI^V421A mutation alone and double mutations. Yars2^G186V alters mitochondrial translation and assembly and activities of complex I, III, and IV, while COI^V421A reduces complex IV activity. However, a single Yars2^G186V or COI^V421A mutation causes mild declines in ATP production and yields relatively mild degeneration of retinal ganglion cells (RGCs). Notably, the synergy between COI^V421A and Yars2^G186V mutations aggravates mitochondrial dysfunction and oxidative stress. Interestingly, COI^V421A mainly promotes apoptosis, and Yars2^G186V contributes to ferroptosis. The combination of two mutations accelerates the degeneration of RGCs and photoreceptors. Strikingly, AAV-mediated Yars2 expression in the mouse retina carrying both Yars2^G186V and COI^V421A mutations corrects the defective translation and ferroptosis arising from the Yars2^G186V mutation and remarkably improves mitochondrial function and causes morphologic and functional recovery of RGCs and photoreceptors. These findings provide mechanistic insights into the pathophysiology of LHON arising from nuclear modifiers and mtDNA mutation(s) and potential therapeutic strategies for LHON and other mitochondrial diseases.
- Optic neuropathy,
- Mitochondrial DNA mutation,
- Mitochondrial tyrosyl-tRNA synthetase,
- Oxidative phosphorylation,
- Ferroptosis,
- Apoptosis,
- Gene therapy

FullText(HTML)

References(72)

References

Ai, C., Li, H., Wang, C., Ji, Y., Wallace, D.C., Qian, J., Zhu, Y., Guan, M.-X., 2025. Vitamin A treatment restores vision failures arising from Leber’s hereditary optic neuropathy-linked mtDNA mutation. JCI Insight 10, e188962.

Badea, T.C., Cahill, H., Ecker, J., Hattar, S., Nathans, J., 2009. Distinct roles of transcription factors Brn3a and Brn3b in controlling the development, morphology, and function of retinal ganglion cells. Neuron 61, 852-864.

Brown, M.D., Torroni, A., Reckord, C.L., Wallace, D.C., 1995. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum. Mutat. 6, 311-325.

Brown, M.D., Trounce, I.A., Jun, A.S., Allen, J.C., Wallace, D.C., 2000. Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. J. Biol. Chem. 275, 39831-39836.

Carelli, V., La Morgia, C., Valentino, M.L., Barboni, P., Ross-Cisneros, F.N., Sadun, A.A., 2009. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim. Biophys. Acta 1787, 518-528.

Chen, B.S., Harvey, J.P., Gilhooley, M.J., Jurkute, N., Yu-Wai-Man, P., 2023a. Mitochondria and the eye-manifestations of mitochondrial diseases and their management. Eye (Lond) 37, 2416-2425.

Chen, B.S., Yu-Wai-Man, P., 2022. From bench to bedside-delivering gene therapy for Leber hereditary optic neuropathy. Cold Spring Harb. Perspect. Med. 12, a041282.

Chen, J.R., Chen, C., Chen, J., Ji, Y., Lian, Y., Zhang, J., Yu, J., Li, X.Y., Qu, J., Guan, M.X., 2023b. Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy. Hum. Mol. Genet. 32, 1539-1551.

Chen, T.H., Wang, H.C., Chang, C.J., Lee, S.Y., 2024. Mitochondrial glutathione in cellular redox homeostasis and disease manifestation. Int. J. Mol. Sci. 25, 1314.

Country, M.W., 2017. Retinal metabolism: a comparative look at energetics in the retina. Brain Res. 1672, 50-57.

Davila-Siliezar, P., Carter, M., Milea, D., Lee, A.G., 2022. Leber hereditary optic neuropathy: new and emerging therapies. Curr. Opin. Ophthalmol. 33, 574-578.

Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., Yang, W.S., et al., 2012. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060-1072.

Du, L., Lin, L., Li, Q., Liu, K., Huang, Y., Wang, X., Cao, K., Chen, X., Cao, W., Li, F., et al., 2019. IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties. Cell Metab. 29, 1363-1375.

Ellouze, S., Augustin, S., Bouaita, A., Bonnet, C., Simonutti, M., Forster, V., Picaud, S., Sahel, J.A., Corral-Debrinski, M., 2008. Optimized allotopic expression of the human mitochondrial prevents blindness in a rat model of mitochondrial dysfunction. Am. J. Hum. Genet. 83, 373-387.

Fan, W., Waymire, K.G., Narula, N., Li, P., Rocher, C., Coskun, P.E., Vannan, M.A., Narula, J., Macgregor, G.R., Wallace, D.C., 2008. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958-962.

Fan, W., Zheng, J., Kong, W., Cui, L., Aishanjiang, M., Yi, Q., Wang, M., Cang, X., Tang, X., Chen, Y., et al., 2019. Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A>G mutation. J. Biol. Chem. 294, 19292-19305.

Ferrington, D.A., Fisher, C.R., Kowluru, R.A., 2020. Mitochondrial defects drive degenerative retinal diseases. Trends Mol. Med. 26, 105-118.

Guarnieri, J.W., Dybas, J.M., Fazelinia, H., Kim, M.S., Frere, J., Zhang, Y., Soto Albrecht, Y., Murdock, D.G., Angelin, A., Singh, L.N., et al., 2023. Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts. Sci. Transl. Med. 15, eabq1533.

Guy, J., Feuer, W.J., Porciatti, V., Schiffman, J., Abukhalil, F., Vandenbroucke, R., Rosa, P.R., Lam, B.L., 2014. Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 55, 841-848.

Hayashi, G., Cortopassi, G., 2015. Oxidative stress in inherited mitochondrial diseases. Free Radic. Biol. Med. 88, 10-17.

Ji, Y., Zhang, J., Lu, Y., Yi, Q., Chen, M., Xie, S., Mao, X., Xiao, Y., Meng, F., Zhang, M., et al., 2020. Complex I mutations synergize to worsen the phenotypic expression of Leber's hereditary optic neuropathy. J. Biol. Chem. 295, 13224-13238.

Jia, Z., Meng, F., Chen, H., Zhu, G., Li, X., He, Y., Zhang, L., He, X., Zhan, H., Chen, M., et al., 2022. Human TRUB1 is a highly conserved pseudouridine synthase responsible for the formation of Ψ55 in mitochondrial tRNAAsn, tRNAGln, tRNAGlu and tRNAPro. Nucleic Acids Res. 50, 9368-9381.

Jiang, P., Jin, X., Peng, Y., Wang, M., Liu, H., Liu, X., Zhang, Z., Ji, Y., Zhang, J., Liang, M., et al., 2016. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation. Hum. Mol. Genet. 25, 584-596.

Jiang, P., Liang, M., Zhang, J., Gao, Y., He, Z., Yu, H., Zhao, F., Ji, Y., Liu, X., Zhang, M., et al., 2015. Prevalence of mitochondrial ND4 mutations in 1281 Han Chinese subjects with Leber's hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 56, 4778-4788.

Jin, X., Zhang, J., Yi, Q., Meng, F., Yu, J., Ji, Y., Mo, J.Q., Tong, Y., Jiang, P., Guan, M.X., 2021a. Leber's hereditary optic neuropathy arising from the synergy between ND1 3635G>A mutation and mitochondrial YARS2 mutations. Invest. Ophthalmol. Vis. Sci. 62, 22.

Jin, X., Zhang, Z., Nie, Z., Wang, C., Meng, F., Yi, Q., Chen, M., Sun, J., Zou, J., Jiang, P., et al., 2021b. An animal model for mitochondrial tyrosyl-tRNA synthetase deficiency reveals links between oxidative phosphorylation and retinal function. J. Biol. Chem. 296, 100437.

Kerrison, J.B., Newman, N.J., 1997. Clinical spectrum of Leber's hereditary optic neuropathy. Clin. Neurosci. 4, 295-301.

Laha, B., Stafford, B.K., Huberman, A.D., 2017. Regenerating optic pathways from the eye to the brain. Science 356, 1031-1034.

Lee, J., Giordano, S., Zhang, J., 2012. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem. J. 441, 523-540.

Levin, L.A., Gordon, L.K., 2002. Retinal ganglion cell disorders: types and treatments. Prog. Retin. Eye. Res. 21, 465-484.

Li, X., Li, W., Dai, X., Kong, F., Zheng, Q., Zhou, X., Lu, F., Chang, B., Rohrer, B., Hauswirth, W.W., et al., 2011. Gene therapy rescues cone structure and function in the 3-month-old rd12 mouse: a model for midcourse RPE65 Leber congenital amaurosis. Invest. Ophthalmol. Vis. Sci. 52, 7-15.

Liang, M., Jiang, P., Li, F., Zhang, J., Ji, Y., He, Y., Xu, M., Zhu, J., Meng, X., Zhao, F., et al., 2014. Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber's hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 55, 1321-1331.

Lin, C.S., Sharpley, M.S., Fan, W., Waymire, K.G., Sadun, A.A., Carelli, V., Ross-Cisneros, F.N., Baciu, P., Sung, E., McManus, M.J., et al., 2012. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc. Natl. Acad. Sci. U. S. A. 109, 20065-20070.

Love, M.I., Huber, W., Anders, S., 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550.

Mashima, Y., Yamada, K., Wakakura, M., Kigasawa, K., Kudoh, J., Shimizu, N., Oguchi, Y., 1998. Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy. Curr. Eye Res. 17, 403-408.

Masland, R.H., 2012. The neuronal organization of the retina. Neuron 76, 266-280.

Mattapallil, M.J., Wawrousek, E.F., Chan, C.C., Zhao, H., Roychoudhury, J., Ferguson, T.A., Caspi, R.R., 2012. The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest. Ophthalmol. Vis. Sci. 53, 2921-2927.

Newman, N.J., Lott, M.T., Wallace, D.C., 1991. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am. J. Ophthalmol. 111, 750-762.

Newman, N.J., Yu-Wai-Man, P., Biousse, V., Carelli, V., 2023. Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management. Lancet Neurol. 22, 172-188.

Pavlou, M., Schon, C., Occelli, L.M., Rossi, A., Meumann, N., Boyd, R.F., Bartoe, J.T., Siedlecki, J., Gerhardt, M.J., Babutzka, S., et al., 2021. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders. EMBO Mol. Med. 13, e13392.

Pertea, M., Pertea, G.M., Antonescu, C.M., Chang, T.C., Mendell, J.T., Salzberg, S.L., 2015. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290-295.

Qu, J., Zhou, X., Zhang, J., Zhao, F., Sun, Y.H., Tong, Y., Wei, Q.P., Cai, W., Yang, L., West, C.E., et al., 2009. Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology 116, 558-564.

Riley, L.G., Heeney, M.M., Rudinger-Thirion, J., Frugier, M., Campagna, D.R., Zhou, R., Hale, G.A., Hilliard, L.M., Kaplan, J.A., Kwiatkowski, J.L., et al., 2018. The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. Haematologica 103, 2008-2015.

Riordan-Eva, P., Sanders, M.D., Govan, G.G., Sweeney, M.G., Da Costa, J., Harding, A.E., 1995. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118 (Pt 2), 319-337.

Sadun, A.A., La Morgia, C., Carelli, V., 2011. Leber's hereditary optic neuropathy. Curr. Treat. Options Neurol. 13, 109-117.

Schaefer, P.M., Rathi, K., Butic, A., Tan, W., Mitchell, K., Wallace, D.C., 2022. Mitochondrial mutations alter endurance exercise response and determinants in mice. Proc. Natl. Acad. Sci. U. S. A. 119, e2200549119.

Shadel, G.S., Horvath, T.L., 2015. Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560-569.

Sies, H., 2007. Total antioxidant capacity: appraisal of a concept. J. Nutr. 137, 1493-1495.

Sies, H., Mailloux, R.J., Jakob, U., 2024. Fundamentals of redox regulation in biology. Nat. Rev. Mol. Cell Biol. 25, 701-719.

Smith, F., Hopton, S., Dallabona, C., Gilberti, M., Falkous, G., Norwood, F., Donnini, C., Gorman, G.S., Clark, B., Taylor, R.W., et al., 2018. Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the YARS2 gene. Haematologica 103, e564-e566.

Song, L., Yu, A., Murray, K., Cortopassi, G., 2017. Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model. Brain Res. 1657, 232-244.

Taylor, R.C., Cullen, S.P., Martin, S.J., 2008. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9, 231-241.

Wallace, D.C., 2005. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359-407.

Wallace, D.C., Lott, M.T., 2017. Leber hereditary optic neuropathy: exemplar of an mtDNA disease. Handb. Exp. Pharmacol. 240, 339-376.

Wallace, D.C., Singh, G., Lott, M.T., Hodge, J.A., Schurr, T.G., Lezza, A.M., Elsas, L.J. 2nd., Nikoskelainen, E.K., 1988. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427-1430.

Wang, C., Youle, R.J., 2009. The role of mitochondria in apoptosis. Annu. Rev. Genet. 43, 95-118.

Wang, C., Zhang, L., Nie, Z., Liang, M., Liu, H., Yi, Q., Wang, C., Ai, C., Zhang, J., Gao, Y., et al., 2024. Mutation of CRYAB encoding a conserved mitochondrial chaperone and antiapoptotic protein causes hereditary optic atrophy. JCI Insight 10, e182209.

Wang, J., Ji, Y., Ai, C., Chen, J.R., Gan, D., Zhang, J., Mo, J.Q., Guan, M.X., 2023. Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation. J. Biomed. Sci. 30, 63.

Weinmann, J., Sollner, J., Abele, S., Zimmermann, G., Zuckschwerdt, K., Mayer, C., Danner-Liskus, J., Peltzer, A., Schuler, M., Lamla, T., et al., 2022. Identification of broadly applicable adeno-associated virus vectors by systematic comparison of commonly used capsid variants in vitro. Hum. Gene. Ther. 33, 1197-1212.

Wong-Riley, M.T., 2010. Energy metabolism of the visual system. Eye Brain 2, 99-116.

Wu, T., Hu, E., Xu, S., Chen, M., Guo, P., Dai, Z., Feng, T., Zhou, L., Tang, W., Zhan, L., et al., 2021. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb) 2, 100141.

Yang, H., Wang, H., Jaenisch, R., 2014. Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nat. Protoc. 9, 1956-1968.

Yasheng, M., Ji, Y., He, Y., Yi, Q., Zhang, H., Shan, W., Wang, K., Zhang, J., Li, Y., Meng, F., et al., 2025. Leber's hereditary optic neuropathy-associated ND1 3733G>C mutation ameliorates the mitochondrial quality control and cellular homeostasis. J. Biol. Chem. 301, 110464.

Yen, M.Y., Wang, A.G., Wei, Y.H., 2006. Leber's hereditary optic neuropathy: a multifactorial disease. Prog. Retin. Eye Res. 25, 381-396.

Yu, J., Liang, X., Ji, Y., Ai, C., Liu, J., Zhu, L., Nie, Z., Jin, X., Wang, C., Zhang, J., et al., 2020. PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy. J. Clin. Invest. 130, 4935-4946.

Yu-Wai-Man, P., Griffiths, P.G., Hudson, G., Chinnery, P.F., 2009. Inherited mitochondrial optic neuropathies. J. Med. Genet. 46, 145-158.

Yu-Wai-Man, P., Newman, N.J., Biousse, V., Carelli, V., Moster, M.L., Vignal-Clermont, C., Klopstock, T., Sadun, A.A., Sergott, R.C., Hage, R., et al., 2025. Five-year outcomes of lenadogene nolparvovec gene therapy in Leber hereditary optic neuropathy. JAMA Ophthalmol. 143, 99-108.

Zeviani, M., Carelli, V., 2021. Mitochondrial Retinopathies. Int. J. Mol. Sci. 23, 210.

Zhang, J., Ji, Y., Chen, J., Xu, M., Wang, G., Ci, X., Lin, B., Mo, J.Q., Zhou, X., Guan, M.X., 2021. Assocation between Leber's hereditary optic neuropathy and MT-ND1 3460G>A mutation-induced alterations in mitochondrial function, apoptosis, and mitophagy. Invest. Ophthalmol. Vis. Sci. 62, 38.

Zhou, M., Xue, L., Chen, Y., Li, H., He, Q., Wang, B., Meng, F., Wang, M., Guan, M.X., 2018. A hypertension-associated mitochondrial DNA mutation introduces an m1G37 modification into tRNAMet, altering its structure and function. J. Biol. Chem. 293, 1425-1438.

Zhu, G., He, Y., Li, X., Xiao, Y., Zhan, H., Duan, M., Guan, M.X., 2025. Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis. J. Biol. Chem. 301, 110334.

Zong, Y., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., Gao, J., 2024. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct. Target Ther. 9, 124.

Relative Articles

Supplements(0)

Cited By

Proportional views