Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.

Authors

Fangbing Chen, Yanhui Liang, Wei Zheng, Aobo Yao, Ning Wang, Huangyao Chen, Zhenpeng Zhuang, Meng Lian, Yu Zhao, Zhen Ouyang, Zhaohai Zhou, Weikai Ge, Qishuai Liu, Yinghua Ye, Liangxue Lai, Kepin Wang

Published in

Science advances. Volume 12. Issue 35. Pages eadu0632. Aug 28, 2026. Epub Aug 26, 2026.

Abstract

The accumulation of mitochondrial DNA (mtDNA) mutations is a primary driver of mitochondrial dysfunction, which is intrinsically linked to aging and various pathologies. POLG, the catalytic subunit of DNA polymerase gamma, is essential for mtDNA replication; notably, a deficiency in its proofreading function precipitates the accumulation of mtDNA mutations. In this study, by combining prime editing with somatic cell nuclear transfer technology, we successfully generated a mitochondrial mutator pig model expressing proofreading-deficient POLG. These pigs exhibited elevated somatic mtDNA mutation loads and recapitulated key premature aging phenotypes, including weight loss, rough hair coat, anemia, structural alterations in the skin and testicular interstitium, increased apoptosis, and the up-regulation of senescence-associated markers, culminating in shortened life span. Given the physiological and metabolic similarities between pigs and humans, this mitochondrial mutator pig model represents an ideal preclinical tool for dissecting the mechanistic role of mtDNA mutations in aging and age-related pathologies and for accelerating the translation of therapeutic strategies.

PMID:
42647635
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.

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