Mitochondrial RNA polymerase is a critical mediator of LPS-induced inflammatory responses and septic shock
- 1Department of Emergency and Critical Care Medicine, Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University
- 2Department of Emergency, Affiliated Hospital of Nanjing University of Chinese Medicine
Abstract
Sepsis, particularly septic shock, is a life-threatening condition driven by a dysregulated inflammatory response. Mitochondria are vital for orchestrating the LPS (lipopolysaccharide)-induced innate immune response. At the core of mitochondrial functionality lies mitochondrial RNA Polymerase (POLRMT). This study delineates POLRMT’s functional role and underlying mechanisms in LPS-induced pro-inflammatory responses across various macrophage models and in vivo. Through multiple genetic strategies, including stable shRNA-mediated knockdown and CRISPR/Cas9-mediated ablation, we demonstrated that POLRMT deficiency in THP-1 human macrophages, peripheral blood mononuclear cells (PBMCs), and murine bone marrow-derived macrophages (BMDMs) consistently attenuated LPS-induced transcriptional upregulation and secretion of key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Conversely, POLRMT overexpression in THP-1 cells augmented these inflammatory responses. LPS-induced enhancements in mitochondrial Complex I activity and ATP content, alongside NFκB activation, were dependent on POLRMT expression. Genetic perturbation of POLRMT directly correlated with altered mitochondrial function and NFκB activity. Pharmacological inhibition of POLRMT with a specific inhibitor IMT1 also suppressed LPS-induced cytokine production, mitochondrial activation, and NFκB activity in vitro. The in vivo studies revealed that knockdown of POLRMT in CD68-expressing cells protected mice from LPS-induced septic shock, reducing mortality and systemic cytokine levels. Oral administration of IMT1 similarly conferred protection against septic shock, correlating with diminished circulating pro-inflammatory cytokines and reduced NFκB activity in murine PBMCs. Collectively, these findings establish POLRMT as a mediator of LPS-induced inflammatory responses in macrophages/monocytes.
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BibTeX
@article{ping2026mitochondrial,
title = {{Mitochondrial RNA polymerase is a critical mediator of LPS-induced inflammatory responses and septic shock}},
author = {Jie Qiong Ping and Tao Guo and Shi Wei Zhang and Cheng Kong and Xiang Yu Gao and Hong Peng Li},
journal = {Biology Direct},
year = {2026},
month = jul,
doi = {10.1186/s13062-026-00917-x},
url = {https://doi.org/10.1186/s13062-026-00917-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondrial RNA polymerase is a critical mediator of LPS-induced inflammatory responses and septic shock
AU - Jie Qiong Ping
AU - Tao Guo
AU - Shi Wei Zhang
AU - Cheng Kong
AU - Xiang Yu Gao
AU - Hong Peng Li
PY - 2026
DA - 2026/07/01
JO - Biology Direct
DO - 10.1186/s13062-026-00917-x
UR - https://doi.org/10.1186/s13062-026-00917-x
AB - Sepsis, particularly septic shock, is a life-threatening condition driven by a dysregulated inflammatory response. Mitochondria are vital for orchestrating the LPS (lipopolysaccharide)-induced innate immune response. At the core of mitochondrial functionality lies mitochondrial RNA Polymerase (POLRMT). This study delineates POLRMT’s functional role and underlying mechanisms in LPS-induced pro-inflammatory responses across various macrophage models and in vivo. Through multiple genetic strategies, including stable shRNA-mediated knockdown and CRISPR/Cas9-mediated ablation, we demonstrated that POLRMT deficiency in THP-1 human macrophages, peripheral blood mononuclear cells (PBMCs), and murine bone marrow-derived macrophages (BMDMs) consistently attenuated LPS-induced transcriptional upregulation and secretion of key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Conversely, POLRMT overexpression in THP-1 cells augmented these inflammatory responses. LPS-induced enhancements in mitochondrial Complex I activity and ATP content, alongside NFκB activation, were dependent on POLRMT expression. Genetic perturbation of POLRMT directly correlated with altered mitochondrial function and NFκB activity. Pharmacological inhibition of POLRMT with a specific inhibitor IMT1 also suppressed LPS-induced cytokine production, mitochondrial activation, and NFκB activity in vitro. The in vivo studies revealed that knockdown of POLRMT in CD68-expressing cells protected mice from LPS-induced septic shock, reducing mortality and systemic cytokine levels. Oral administration of IMT1 similarly conferred protection against septic shock, correlating with diminished circulating pro-inflammatory cytokines and reduced NFκB activity in murine PBMCs. Collectively, these findings establish POLRMT as a mediator of LPS-induced inflammatory responses in macrophages/monocytes.
SN - 1745-6150
ER -