433: Lactate, HSP90α and the Mitochondrial Switch

Wu G et al., Proceedings of the National Academy of Sciences - This episode examines a PNAS study that identifies site-specific lactylation of HSP90α as a metabolic signal linking glycolysis to mitochondrial biogenesis in ovarian cells. Lactylation at K58 and K616 modulates HSP90α phosphorylation, enabling nuclear import of PGC1α and LRPGC1, boosting mitochondrial number, cholesterol import, estradiol synthesis, and follicle growth; CREBBP, ACSS2 and GTPSCS participate in the lactylation pathway. Key terms: HSP90α, lactylation, PGC1α, mitochondrial biogenesis, estradiol.

Study Highlights:
The authors show that sodium lactate promotes HSP90α lactylation at K58 and K616 via CREBBP and lactyl-CoA synthesis (ACSS2/GTPSCS). K58 lactylation enhances ULK1 recruitment and S39 phosphorylation while K616 lactylation blocks CDK5-mediated S596 phosphorylation, together enabling HSP90α to chaperone PGC1α and LRPGC1 into the nucleus. Nuclear PGC1α/LRPGC1 activate NRF1/2 targets (Tfb1m, Tfb2m, Tfam) to drive mitochondrial biogenesis, increase mitochondrial cholesterol import and raise estradiol production, with in vivo lactate raising ovarian mtDNA, TOM20, estradiol and antral follicle number.

Conclusion:
Site-specific lactylation of HSP90α integrates glycolytic flux with chaperone and phosphorylation control to promote PGC1α/LRPGC1 nuclear import, mitochondrial biogenesis and steroidogenic output in ovarian cells, revealing a metabolite-dependent regulatory axis with potential implications for ovarian function and fertility.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis

First author:
Wu G

Journal:
Proceedings of the National Academy of Sciences

DOI:
10.1073/pnas.2528979123

Reference:
Wu G., Li H., He T., et al. HSP90α lactylation orchestrates PGC1α and LRPGC1 nuclear translocation driving mitochondrial biogenesis. PNAS. 2026;123(30):e2528979123. doi:10.1073/pnas.2528979123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
More at basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/hsp90a-lactylation-mito-biogenesis

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-23.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the main mechanistic narrative from lactate signaling to HSP90α lactylation, ULK1/CDK5-regulated phosphorylation, nuclear import of PGC1α/LRPGC1, NRF1/2-driven transcription, mitochondrial biogenesis, cholesterol import, and in vivo hormonal/follicle outcomes.
- transcript topics: Lactate as signaling molecule and lactylation concept; HSP90α lactylation at K58 and K616; CREBBP as the lactyltransferase and lactyl-CoA synthesis pathway; ULK1 and CDK5 regulation of S39 and S596 phosphorylation; HSP90α-mediated nuclear import of PGC1α and LRPGC1; NRF1/NRF2 target gene activation (TFB1M, TFB2M, Tfam) and mitochondrial biogenesis

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claim...