Sph-mediated mtDNA release and autophagy-dependent ferroptosis contribute to Staphylococcus aureus-induced mastitis.

Authors

Yunfei Wei, Xinyu Zhao, Ziyi Yin, Yanmin Zhang, Yaxin Zhai, Baihe Zhan, Yeling Wang, Jiakang He, Jianfeng Wang, Xuming Deng, Lei Xu, Haihua Feng

Published in

PLoS pathogens. Volume 22. Issue 9. Pages e1014644. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Staphylococcus aureus (S. aureus), a major pathogen of mastitis, employs a diverse arsenal of virulence factors to invade and disrupt mammary tissues, thereby eliciting a complex and dysregulated inflammatory response. Sphingomyelin phosphodiesterase (Sph) has emerged as a key virulence determinant of S. aureus; however, its potential role and underlying mechanisms in mastitis remain elusive. In this study, we demonstrate that Sph deficiency significantly suppresses S. aureus-induced ferroptosis. Mechanistically, Sph disrupts mitochondrial cristae through interaction with Mic60, a core component of the mitochondrial contact site and cristae-organizing system (MICOS). Sph-mediated cytosolic mitochondrial DNA (mtDNA) released is sensed by cyclic GMP-AMP synthase (cGAS), leading to activation of the STING signaling pathway, which further triggers the recruitment of GPX4 into the autophagy-lysosome pathway for degradation. Collectively, our study unveils a novel pathogenic mechanism whereby the S. aureus virulence factor Sph perturbs mitochondrial homeostasis, and engages the cGAS-STING axis to promote GPX4 degradation and ferroptosis, highlighting Sph as a potential therapeutic target for S. aureus-associated mastitis.

PMID:
42809547
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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