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Tomar, A. ; Gómez Velázquez, M. ; Gerlini, R. ; Comas-Armangue, G. ; Makharadze, L. ; Kolbe, T.* ; Boersma, A.* ; Dahlhoff, M.* ; Burgstaller, J.P.* ; Lassi, M. ; Darr, J. ; Toppari, J.* ; Virtanen, H.* ; Kühnapfel, A.* ; Scholz, M.* ; Landgraf, K.* ; Kiess, W.* ; Vogel, M.* ; Gailus-Durner, V. ; Fuchs, H. ; Marschall, S. ; Hrabě de Angelis, M. ; Kotaja, N.* ; Körner, A. ; Teperino, R.

Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Nature, 27 (2024)

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Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)¹, which influences offspring development and adult phenotypes^1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood⁸. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Induced Paternal Obesity; Spermatogenesis; Embryo; Spermatozoa; Dysfunction; Biology; Cells

ISSN (print) / ISBN 0028-0836

e-ISSN 1476-4687

Journal Nature

Quellenangaben Pages: 27

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)

Grants Christian-Hagedorn project - German Diabetes Society
Minerva Association (ARCHES Prize 2016)
Helmholtz Association (Helmholtz ERC Recognition Award)
Fritz-Thyssen Stiftung
Sigrid Juselius Foundation
Academy of Finland
Pediatric Research Foundation
Turku University Hospital
Novo Nordisk Foundation
Jalmari and Rauha Ahokas Foundation
German Research Foundation (DFG) for the Clinical Research Center 'Obesity Mechanisms
German Diabetes Research Center (DZD Next Grant 2019)