The mitochondrial respiratory chain supports inflammation

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t) in WT and NDI1 BMDMs (n = 5 WT; n = 12 NDI1). c, combined OCR in WT and NDI1 BMDMs (n = 9 for each genotype). d, Basal OCR in WT and NDI1 BMDM after 1 hour of treatment with 100 nM or 500 nM piericidin A (n = 13 carriers for each genotype; n = 9 100 nM piericidin A for each genotype; n = 4,500 nM piericidin A for each genotype genotype). e, NAD ratio⁺/ NADH in WT and NDI1 BMDM after 4 hours of treatment with or without LPS (100 ng ml^-1) in the presence or absence of piericidin A (500 nm) (n = 3 WT LPS + pyrcidin A; n = 4 all other treatments). f, Production rate H₂Oh₂ in WT and NDI1 BMDMs in the presence of succinate (500 μM) with or without pyricidin A (500 nM) treatment (n = 9). g, thermal map of significantly altered metabolites in WT and NDI1 BMDM treated only by LPS (100 ng ml^-1), pyricidin A alone (500 nM) or both LPS and piericidin A for 4 hours. The relative amount of each metabolite is displayed as a z-score in the series (red, high; blue, low) (n = 5 for all treatments). h, arbitrary succinate units in WT and NDI1 BMDM with or without LPS (100 ng ml ^-1) and piericidin A (500 nM) for 4 hours (n = 5 for all treatments). Data represent mean ± sem * P <0.05, two-way t-test (b, P = 0.0001), similar to analysis with post-special bale test for multiple comparisons (d, * P = 0.0008 WT UT / 100 nM, * P = 0.0047 WT UT / 500 nm, e, * P = 0.006 WT UT / WT piericidin A, * P = 0.0034 WT LPS / WT LPS + piericidin A; f, * P = 0.0465 WT succinate / WT succinate + piericidin A, * P 0.0493 NDI1 succinate / NDI1 succinate + piericidin A; h, * P = 0.0478), or ANOVA with Fisher's LSD (d). n indicates the number of individual mice. Parts of this figure were created with BioRender.com. Merit: Nature Immunology (2022). DOI: 10.1038 / s41590-022-01185-3 “width =” 800 “height =” 530 “/>

Expression of NDI1 confers resistance to mitochondrial complex I inhibitor, piericidin A. a, mitochondrial electron transport chain scheme in WT (above) and NDI1-expressing (below) BMDM during LPS stimulation. Piericidin A inhibiting mitochondrial complex I on electron flow is saved by NDI1 expression. IMM, inner mitochondrial membrane; RET, reverse electron transport. b, NDI1 mRNA levels (ΔΔC_t) in WT and NDI1 BMDM (n = 5 WT; n = 12 NDI1). c, combined OCR in WT and NDI1 BMDMs (n = 9 for each genotype). d, Basal OCR in WT and NDI1 BMDM after 1 hour of treatment with 100 nM or 500 nM piericidin A (n = 13 carriers for each genotype; n = 9 100 nM piericidin A for each genotype; n = 4,500 nM piericidin A for each genotype genotype). e, NAD⁺Ratio / NADH in WT and NDI1 BMDM after 4 hours of treatment with or without LPS (100 ng ml^–1) in the presence or absence of piericidin A (500 nm) (n = 3 WT LPS + pyrcidin A; n = 4 all other treatments). f, velocity H₂Oh₂ production in WT and NDI1 BMDMs in the presence of succinate (500 μM) with or without treatment with piericidin A (500 nM) (n = 9). g, Thermal map of significantly altered metabolites in WT and NDI1 BMDM treated with LPS (100 ng ml^–1) alone, only piericidin A (500 nM) or both LPS and piericidin A for 4 hours. The relative amount of each metabolite is displayed as a z-score in the series (red, high; blue, low) (n = 5 for all treatments). h, arbitrary succinate units in WT and NDI1 BMDM with or without LPS (100 ng ml^–1) and piericidin A (500 nm) for 4 hours (n = 5 for all treatments). Data are mean ± sem * P Nature Immunology (2022). DOI: 10.1038 / s41590-022-01185-3

Researchers at Northwestern Medicine recently found that the respiratory chain of mitochondria – a series of protein complexes needed for cellular respiration and energy production – is needed to activate another protein complex associated with inflammation and progression of chronic diseases, according to a study published in Nature immunology.

“Our study found that inhibition of the mitochondrial respiratory chain suppresses NLRP3 activation of inflammation genetically and pharmacologically, ”said Dr. Naudip Chandel, MD David W. Kugell, professor of medicine in the Department of Pulmonary and Intensive Care, Biochemistry and Molecular Genetics, and senior author of the study.

Inflammasoma NLRP3 is a protein complex which is activated by viral or bacterial infections and can also cause tissue damage and progression of chronic diseases including obesity, Alzheimer’s disease and type 2 diabetes, causing the release of proinflammatory cytokines.

Previous work has demonstrated that NLRP3 inflammation is regulated by mitochondria, in particular by generating mitochondrial reactive oxygen species (ROS), in particular superoxide and hydrogen peroxide.

In the current study, Chandel and his team used genetic sequencing and pharmacological strategies to study macrophages (specialized white blood cells) and investigate the need for mitochondrial ROS to activate the NLRP3 inflammatory hormone.

To their surprise, they found that mitochondrial ROS were not needed. In addition, inhibitors of the mitochondrial respiratory chain complexes I, II, III, and V – all of which are necessary for proper energy production in the cell – prevented the activation of NLRP3 by the inflammatory mass.

They also found that creatine, which is naturally produced by the body and is a widely available dietary supplement, increases the level of phosphocreatine that is needed for proper energy production inside cells, and is depleted by respiratory chain inhibitors, which in turn also supports inflammation activation.

“The discovery that creatine and phosphocreatine are linked to inflammation opens up a new pathway of research with possible implications for creatine,” Chandel said.

According to the authors, current results emphasize that the mitochondrial respiratory chain supports the activation of the NLRP3 inflammatory mass through phosphocreatine-dependent energy generation and is completely independent of mitochondrial ROS.

Chandel said his team is now interested in investigating how mitochondria control inflammation in the context of influenza and Alzheimer’s disease.

“Tools and Conceptual framework we created in this article, allow us and others to study how mitochondria regulate different cytokines in different diseases, ”Chandel said.

Oxidized DNA caused by the flu virus activates inflammation

Additional information:
Leah K. Billingham et al., An electron transport chain in mitochondria is required for activation of the NLRP3 inflammatory mass, Nature Immunology (2022). DOI: 10.1038 / s41590-022-01185-3

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Northwestern University

Citation: Mitochondrial respiratory chain supports inflammation (2022, May 13) obtained May 13, 2022 from https://medicalxpress.com/news/2022-05-mitochondrial-respiratory-chain-sustains-inflammation.html

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