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Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.

ABSTRACT: Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro. MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation.

SUBMITTER: Purandare N

PROVIDER: S-EPMC9633742 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.

Purandare Neeraja N Kunji Yusef Y Xi Yue Y Romero Roberto R Gomez-Lopez Nardhy N Fribley Andrew A Grossman Lawrence I LI Aras Siddhesh S

iScience 20221012 11

Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of system ...[more]

PMID: 36339251

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Project description:BACKGROUND:Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) is one of the major pathogenic factors of chronic periodontitis (CP). Few reports on the correlation between P. gingivalis-LPS and cognitive function exist. Thus, the present study aimed to investigate the effects of P. gingivalis-LPS on cognitive function and the associated underlying mechanism in C57BL/6 mice. METHODS:The C57BL/6 mice were injected with P. gingivalis-LPS (5 mg kg-1) either with or without Toll-like receptor 4 (TLR4) inhibitor (TAK-242, 5 mg kg-1). After 7 days, behavioral alterations were assessed with the open field test (OFT), Morris water maze (MWM) test, and passive avoidance test (PAT). The activation of astrocytes and microglia in the cerebral cortex and hippocampus of mice was observed by immunohistochemistry. The expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), TLRs (TLR2, TLR3, and TLR4), and CD14 and the activation of the NF-κB signaling pathway (IRAK1, p65, and p-p65) in the cerebral cortex of the mice were evaluated by RT-PCR, ELISA, and western blot. RESULTS:The OFT showed that P. gingivalis-LPS did not affect the initiative and activity of mice. Administration of P. gingivalis-LPS significantly impaired spatial learning and memory during the MWM test and attenuated the ability of passive avoidance learning during the PAT. Both astrocytes and microglia were activated in the cortex and hippocampus. The messenger RNA (mRNA) and protein expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) was upregulated by P. gingivalis-LPS in the cortex. In addition, the TLR4/NF-κB signaling pathway was activated (TLR4, CD14, IRAK1, and p-p65). These effects were effectively alleviated by TAK-242. CONCLUSIONS:Administration of P. gingivalis-LPS can lead to learning and memory impairment in C57BL/6 mice. This impairment is mediated by activation of the TLR4 signaling pathway. Our study suggests that P. gingivalis-LPS-induced neuroinflammation plays an important role in cognitive impairment. It also reveals that endotoxins of periodontal pathogens could represent a risk factor for cognitive disorders.

Dataset Information

Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.

Publications

Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway.

Similar Datasets

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