Authors
Gang Wu, Hongmin Li, Tong He, Min Chen, Xiaoyu Jiang, Mengli Wei, Lei Zhou, Chengyu Li, Jingli Tao, Zhaojun Liu, Ming Shen, Honglin Liu
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 30. Pages e2528979123. Jul 28, 2026. Epub Jul 21, 2026.
Abstract
Mitochondrial biogenesis is a fundamental process that ensures energy supply and supports steroidogenesis in ovarian cells. Lactate has recently been identified as a signaling metabolite that promotes mitochondrial biogenesis; however, the underlying regulatory mechanisms remain poorly defined. Here, we identify Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90α) lactylation as a key mediator that links glycolytic metabolism to mitochondrial function. Specifically, lactylation of HSP90α at K58 recruits ULK1, thereby enhancing phosphorylation at S39; lactylation at K616 prevents CDK5-mediated phosphorylation at S596. This dual regulation facilitates the nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and its isoform LRPGC1, which activate NRF1/2-dependent transcription of mitochondrial biogenesis genes, such as Tfb1m, Tfb2m, and Tfam. Functionally, mitochondrial mass expansion both enhances cellular energy metabolism and promotes cholesterol import into mitochondria, thereby driving estrogen biosynthesis. Together, these findings reveal a lactate-HSP90α-PGC1α/LRPGC1 axis that metabolically couples glycolysis to mitochondrial biogenesis and reproductive hormone production, providing insights into the epigenetic regulation of follicular development.
PMID:
42479841
Bibliographic data and abstract were imported from PubMed on 22 Jul 2026.
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