248: Disruption of PIKfyve triggers lysosomal repair and mitochondrial adaptation

Kutchukian C et al., Nature Communications - Disruption of the PIKfyve/Fig4/Vac14 complex drives ULK1-dependent trafficking of PI4KIIα and ATG9A to lysosomes, elevating lysosomal PI(4)P to promote membrane repair and induce mitochondrial fragmentation with increased respiration. Key terms: PIKfyve, PI4KIIα, PI(4)P, ULK1, lysosomal repair.

Study Highlights:
PIKfyve complex disruption or pharmacological inhibition reduces mTORC1 signaling, activating ULK1 and driving ATG9A-dependent trafficking of PI4KIIα from the TGN to lysosomes. PI4KIIα accumulation elevates lysosomal PI(4)P, recruiting OSBP/ORP proteins to transfer cholesterol and phosphatidylserine and enhance lysosomal membrane repair. Elevated lysosomal PI(4)P recruits ORP1L at ER–lysosome–mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria, Drp1 recruitment, mitochondrial fragmentation, and increased oxygen consumption. Inhibition of ULK1 or PI4KIIα or mitochondrial targeting of Sac1 reverses these lysosomal and mitochondrial phenotypes.

Conclusion:
A ULK1-dependent PI4KIIα–PI(4)P pathway links PIKfyve complex dysfunction to coordinated lysosomal membrane repair and adaptive mitochondrial remodeling

Music:
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Article title:
Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis

First author:
Kutchukian C

Journal:
Nature Communications

DOI:
10.1038/s41467-025-65798-6

Reference:
Kutchukian C., Casas M., Dixon R. E., Dickson E. J. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis. Nature Communications. 2025;16:10761. https://doi.org/10.1038/s41467-025-65798-6

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/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-01-03.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's coverage of the paper's mechanism: acute PIKfyve disruption activates a ULK1-dependent PI4KIIα/ATG9A trafficking program, increases lysosomal PI(4)P, recruits OSBP/ORP proteins for membrane repair, enhances ER–lysosome–mitochondria three-way contacts with ORP1L and Drp1-driven mitochondrial fra
- transcript topics: ULK1-dependent trafficking of PI4KIIα and ATG9A from the TGN to lysosomes; PI(4)P redistribution to lysosomes and PI4KIIα relocation from the TGN; OSBP/ORP-mediated lipid transfer and lysosomal membrane repair (PITT pathway); ER–lysosome–mitochondria three-way contact sites and ORP1L/Drp1 recruitment; Mitochondrial fragmentation and enhanced respiration (Seahorse data); ULK1/mTOR signaling modulation

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Acute PIKfyve inhibition reduces mTORC1 signaling and ULK1 activation
- ULK1-dependent trafficking of PI4KIIα and ATG9A from the TGN to lys...