Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure

Z Zhuqing Wang (School of Molecular Biosciences, Washington State University) Y Yasuhiro Yamauchi (Department of Applied Chemistry, Faculty of Engineering) S Sheng Chen (Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.) H Huili Zheng (School of Molecular Biosciences, Washington State University) M Monika A. Ward (Yanagimachi Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii) W Wei Yan

Abstract

Paternal epigenetic inheritance remains mechanistically unresolved. Recent studies propose that environmental exposures induce mitochondrial DNA (mtDNA)-dependent transcription in sperm during epididymal transit, altering small RNA content and offspring phenotypes. Here, we show that mature murine sperm are effectively devoid of mtDNA, precluding mtDNA-dependent transcription, and that sperm-borne mitochondrial RNAs originate during spermatogenesis. Testicular sperm transmitted diet-induced metabolic traits as efficiently as, and in most cohorts more efficiently than, epididymal sperm. These findings establish testicular inheritance independent of sperm mtDNA transcription and epididymal exposure.

Article Details

Volume / Issue Vol. 123, Issue 24
Published June 16, 2026
ISSN 0027-8424
Publisher National Academy of Sciences

Authors (6)

Z

Zhuqing Wang

School of Molecular Biosciences, Washington State University

Y

Yasuhiro Yamauchi

Department of Applied Chemistry, Faculty of Engineering

S

Sheng Chen

Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

H

Huili Zheng

School of Molecular Biosciences, Washington State University

M

Monika A. Ward

Yanagimachi Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii

W

Wei Yan