The Journal of biological chemistryJul 16, 2026

O-GlcNAcylation acts as a signal between mitochondria and nucleus to control passive transport through the nuclear pore

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 17, 2026

Abstract

Phenformin treatment leads to restricted passive nuclear transport in HeLa cells in a dose and time-dependent manner.

The nuclear pore complex (NPC) serves as the gateway for transport between the nucleus and cytoplasm, with size limitations for passive diffusion in healthy cells.
Aging and disease are associated with NPC deterioration, resulting in increased passive transport.
Inhibition of the mitochondrial electron transport chain also restricts passive nucleocytoplasmic transport.
Phenformin treatment reduces the expression of O-GlcNAc transferase (OGT), which lowers global O-GlcNAcylation and decreases O-GlcNAcylation of the NPC protein Nup98.
Inhibition of OGT restricts passive transport, while increased O-GlcNAcylation can reverse the effects of phenformin.

Simplified

The nuclear pore complex (NPC) is the single gateway between the nucleus and the cytoplasm, and in healthy cells there is a size threshold for passive diffusion across the NPC. In aging and disease, the NPC deteriorates, leading to promiscuous passive transport. We have previously showed that NPC protein expression is required for biguanide-induced lifespan extension, mTOR inhibition, and further that biguanide treatment leads to restriction of passive nuclear transport, but the underlying changes leading to this restriction were not identified. Here, we use fluorescent dextran transport and biochemical assays in HeLa cells to clarify the mechanism by which biguanide phenformin alters NPC permeability. We find phenformin treatment in HeLa cells leads to restricted passive nuclear transport in a dose and time-dependent manner. Multiple inhibitors of the mitochondrial electron transport chain (ETC) also restrict passive nucleocytoplasmic transport. Critically, phenformin reduced expression of O-GlcNAc transferase (OGT), lowering global O-GlcNAcylation and locally decreasing O-GlcNAcylation of Nup98. OGT inhibition alone restricts passive transport, while increasing O-GlcNAcylation reverses phenformin's effects. These results identify O-GlcNAc as a mitochondrial-nuclear signal and show that ETC inhibition rapidly modulates nucleocytoplasmic transport via NPC post-translational modification in human cancer cells.

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O-GlcNAcylation acts as a signal between mitochondria and nucleus to control passive transport through the nuclear pore

Abstract

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