Abstract
Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded…
Abstract
Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
Data availability
The data supporting the findings of this study are available from the corresponding authors upon request. The RNA-seq, RNC-seq, tRNA m1A seq, and tRNA seq analysis data generated in this study have been deposited in the Sequence Read Archive (SRA) database under accession code PRJNA1104793, PRJNA1204926, PRJNA1358275 and PRJNA1358279. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD070509. All data necessary for confirming the conclusions of the article are present within the article and/or the Supplementary information. Source data for the figures and Supplementary Figs. are provided as a Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 32430049) (Q.Z.), National Key R&D Program of China (2021YFA0804903) (Q.Z.), Programme of Introducing Talents of Discipline to Universities (B14036) (Q.Z.), the Guangdong Basic and Applied Basic Research Foundation (2023B1515120089) (Q.Z.). Qinghua Zhou also gratefully acknowledges the support of the K.C. Wong Education Foundation. We thank the Caenorhabditis Genetic Center (CGC) and the National BioResource Project (NBRP) for strains; Dr Tian Y (the Genetics and Developmental Biology, Chinese Academy of Sciences) and Dr Miao L (the Key Laboratory of RNA Biology, Chinese Academy of Sciences) for providing the worm strains; Dr Yan GR (Biomedicine Research Center, the Third Affiliated Hospital of Guangzhou Medical University) for helping with the demethylation activity analysis of ALKB-1.
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These authors contributed equally: Zhenhuan Luo, Yimin Li.
Authors and Affiliations
Department of Cardiology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
Zhenhuan Luo 1.
Shantou Clinical Medical College of Jinan University (Shantou Central Hospital), Jinan University, Shantou, Guangdong, China
Zhenhuan Luo, Chenyang He, Dan Wu, Wenyu Dai, Hao Wang & Qinghua Zhou 1.
College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
Zhenhuan Luo, Chenyang He, Dan Wu, Wenyu Dai, Jing Yang & Qinghua Zhou 1.
Department of pathogen biology, school of medicine, Jinan University, Guangzhou, Guangdong, China
Yimin Li & Qin-Li Wan 1.
The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, China
Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang & Qin-Li Wan 1.
Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
Brian L. Harry 1.
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regeneration Medicine, Jinan University, Guangzhou, Guangdong, China
Zhenyu Ju 1.
Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas Department of Basic Sciences, School of Medicine, University of Crete Heraklion, Crete, Greece
Nektarios Tavernarakis 1.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China
Qinghua Zhou 1.
National Engineering Research Center of Genetic Medicine, Guangzhou, Guangdong, China
Qinghua Zhou
Authors
- Zhenhuan Luo
- Yimin Li
- Chenyang He
- Dan Wu
- Wenyu Dai
- Liubing Hu
- Jing Yang
- Brian L. Harry
- Zhenyu Ju
- Nektarios Tavernarakis
- Hao Wang
- Qin-Li Wan
- Qinghua Zhou
Contributions
Q.Z. and Q-L.W. conceptualized and conceived the study. Q. Z., Q-L.W. and Z.L. designed the study. Z.L., Y.L., C.H., D.W., W.D., L.H. and J.Y. performed the experiments. Z.L. and Y.L. analyzed the data. Q-L.W. and Z.L. wrote the manuscript. Q.Z., Q-L.W., Z.J., N.T. and H.W. reviewed and edited the manuscript.
Corresponding authors
Correspondence to Hao Wang, Qin-Li Wan or Qinghua Zhou.
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Luo, Z., Li, Y., He, C. et al. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68813-6
Received: 17 April 2025
Accepted: 18 January 2026
Published: 29 January 2026
DOI: https://doi.org/10.1038/s41467-026-68813-6