ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance.

Authors

• Teresa T Liu
• Mia J Carrarini
• Livianna K Myklebust
• Kegan O Skalitzky
• Nathalie El-Khoury
• Ian J Sipula
• Alexander Chang
• Vishal Soman
• Ailing Liu
• Nnamdi Ihejirika
• Uma R Chandran
• Michael J Jurczak
• William A Ricke
• Donald B DeFranco
• Laura E Pascal

Publication/Presentation Date

10-21-2025

Abstract

Declining mitochondrial function is an established feature of aging and contributes to most aging-related diseases through its impact on various pathologies such as chronic inflammation, fibrosis and cellular senescence. Our recent work suggests that benign prostatic hyperplasia, which is an aging-related disease frequently associated with inflammation, fibrosis and senescence, is characterized by a decline in mitochondrial function. Here, we utilize glycolytic restriction and pharmacologic inhibition of the mitochondrial electron transfer chain complex I to promote mitochondrial dysfunction and identify the cellular processes impacted by declining mitochondrial function in benign prostate stromal cells. Using this model, we show that mitochondrial dysfunction induced alterations in cell-cell and cell-matrix adhesion, elevated fibronectin expression, resistance to anoikis and stress-induced premature senescence (SIPS). We also showed that ablation of ZC3H4, a transcription termination factor implicated in anoikis-resistance and reduced in BPH relative to normal prostates, phenocopied various phenotypes in the human BHPrS1 prostate stromal cell line that resulted from inhibition of complex I. Furthermore, ZC3H4 ablation resulted in the elevation of mitochondrial superoxide (mtROS) and mitochondrial membrane potential, altered mitochondrial morphology and NAD

Volume

16

Issue

1

First Page

741

Last Page

741

ISSN

2041-4889

Published In/Presented At

Liu, T. T., Carrarini, M. J., Myklebust, L. K., Skalitzky, K. O., El-Khoury, N., Sipula, I. J., Chang, A., Soman, V., Liu, A., Ihejirika, N., Chandran, U. R., Jurczak, M. J., Ricke, W. A., DeFranco, D. B., & Pascal, L. E. (2025). ZC3H4, a novel regulator of mitochondrial complex I, impacts prostate stromal cell senescence, attachment, adhesion and anoikis resistance. Cell death & disease, 16(1), 741. https://doi.org/10.1038/s41419-025-08027-8

Disciplines

Medicine and Health Sciences

PubMedID

41120279

Department(s)

Fellows and Residents

Document Type

Article