Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs
A. Tomar Helmholtz Zentrum München / German Center for Diabetes Research
Helmholtz Zentrum München / German Center for Diabetes Research
Leipzig University
N. Kotaja University of Turku
M. Hrabě de Angelis Helmholtz Zentrum München / German Center for Diabetes Research
Helmholtz Zentrum München / German Center for Diabetes Research
H. Fuchs Helmholtz Zentrum München / German Center for Diabetes Research
Helmholtz Zentrum München / German Center for Diabetes Research
M. Vogel Leipzig University
W. Kiess Leipzig University
Leipzig University
Leipzig University
Leipzig University
H. Virtanen University of Turku
J. Toppari University of Turku
J. Darr Helmholtz Zentrum München / German Center for Diabetes Research
M. Lassi Helmholtz Zentrum München / German Center for Diabetes Research
Jörg Burgstaller University of Veterinary Medicine Vienna / Boku University
University of Veterinary Medicine Vienna
University of Veterinary Medicine Vienna
University of Veterinary Medicine Vienna / BOKU University
L. Makharadze Helmholtz Zentrum München / German Center for Diabetes Research
G. Comas-Armangué Helmholtz Zentrum München / German Center for Diabetes Research
M. Gomez-Velazquez Helmholtz Zentrum München / German Center for Diabetes Research
R. Gerlini Helmholtz Zentrum München / German Center for Diabetes Research
Nature Portfolio
Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. 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.
English
2024
This work is licensed under a
CC BY 4.0 - Creative Commons Attribution 4.0 International License.
CC BY 4.0 International
http://creativecommons.org/licenses/by/4.0/
Energy Metabolism; Epigenetics; Animals; Male; Spermatozoametabolism; Mice; RNA; Mitochondrial Genetics Metabolism; Female; Epigenesis, Genetic;