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The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes

Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathol...

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Autores principales: Chang, Yen-Hsiang, Lin, Hung-Yu, Shen, Feng-Chih, Su, Yu-Jih, Chuang, Jiin-Haur, Lin, Tsu-Kung, Liou, Chia-Wei, Lin, Ching-Yi, Weng, Shao-Wen, Wang, Pei-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403198/
https://www.ncbi.nlm.nih.gov/pubmed/32849261
http://dx.doi.org/10.3389/fendo.2020.00445
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author Chang, Yen-Hsiang
Lin, Hung-Yu
Shen, Feng-Chih
Su, Yu-Jih
Chuang, Jiin-Haur
Lin, Tsu-Kung
Liou, Chia-Wei
Lin, Ching-Yi
Weng, Shao-Wen
Wang, Pei-Wen
author_facet Chang, Yen-Hsiang
Lin, Hung-Yu
Shen, Feng-Chih
Su, Yu-Jih
Chuang, Jiin-Haur
Lin, Tsu-Kung
Liou, Chia-Wei
Lin, Ching-Yi
Weng, Shao-Wen
Wang, Pei-Wen
author_sort Chang, Yen-Hsiang
collection PubMed
description Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1β), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D.
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spelling pubmed-74031982020-08-25 The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes Chang, Yen-Hsiang Lin, Hung-Yu Shen, Feng-Chih Su, Yu-Jih Chuang, Jiin-Haur Lin, Tsu-Kung Liou, Chia-Wei Lin, Ching-Yi Weng, Shao-Wen Wang, Pei-Wen Front Endocrinol (Lausanne) Endocrinology Background: Plenty of evidence suggested that chronic low-grade inflammation triggered by innate immunity activation contributes to the pathogenesis of type 2 diabetes (T2D). Using the trans-mitochondrial cybrid cell model, we have demonstrated that mitochondria independently take part in the pathological process of insulin resistance (IR) and pro-inflammatory phenotype in cybrid cells harboring mitochondrial haplogroup B4, which are more likely to develop T2D. The mitochondrial network is more fragmented, and the expression of fusion-related proteins is low in Cybrid B4. We also discovered the causal role of mitochondrial dynamics (mtDYN) proteins in regulating IR in this cybrid model, and the bidirectional interaction between mtDYN and mitochondrial oxidative stress is considered etiologically important. In this study, we further investigated whether mtDYN bridges the gap between nutrient excess and chronic inflammation in T2D. Methods: Trans-mitochondrial cybrid cells derived from the 143B human osteosarcoma cell line were cultured in a medium containing glucose (25 mM) with or without saturated fatty acid (0.25 mM BSA-conjugated palmitate), and the expression of innate immunity/inflammasome molecules was compared between cybrid B4 (the major T2D-susceptible haplogroup among the Chinese population) and cybrid D4 (the major T2D-resistant haplogroup among the Chinese population). We investigated the causal relationship between mtDYN and nutrient excess-induced inflammation in cybrid B4 by genetic manipulation of mtDYN and by pharmacologically inhibiting mitochondrial fission using the Drp1 inhibitor, mdivi-1, and metformin. Results: Under nutrient excess with high fatty acid, cybrid B4 presented increased mitochondrial pro-fission profiles and enhanced chronic inflammation markers (RIG-I, MDA5, MAVS) and inflammasome (NLRP3, Caspase-1, IL-1β), whereas the levels in cybrid D4 were not or less significantly altered. In cybrid B4 under nutrient excess, overexpression of fusion proteins (Mfn1 or Mfn2) significantly repressed the expression of innate immunity/inflammasome-related molecules, while knockdown had a less significant effect. On the contrary, knockdown of fission proteins (Drp1 or Fis1) significantly repressed the expression of innate immunity/inflammasome-related molecules, while overexpression had a less significant effect. In addition, Drp1 inhibitor mdivi-1 and metformin inhibited mitochondrial fission and attenuated the pro-inflammation expression as well. Conclusion: Our results discovered the causal relationship between mtDYN and nutrient excess-induced chronic inflammation in a diabetes-susceptible cell model. Targeting mtDYN by direct interfering pro-fission can be a therapeutic intervention for chronic inflammation in T2D. Frontiers Media S.A. 2020-07-29 /pmc/articles/PMC7403198/ /pubmed/32849261 http://dx.doi.org/10.3389/fendo.2020.00445 Text en Copyright © 2020 Chang, Lin, Shen, Su, Chuang, Lin, Liou, Lin, Weng and Wang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Chang, Yen-Hsiang
Lin, Hung-Yu
Shen, Feng-Chih
Su, Yu-Jih
Chuang, Jiin-Haur
Lin, Tsu-Kung
Liou, Chia-Wei
Lin, Ching-Yi
Weng, Shao-Wen
Wang, Pei-Wen
The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title_full The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title_fullStr The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title_full_unstemmed The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title_short The Causal Role of Mitochondrial Dynamics in Regulating Innate Immunity in Diabetes
title_sort causal role of mitochondrial dynamics in regulating innate immunity in diabetes
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403198/
https://www.ncbi.nlm.nih.gov/pubmed/32849261
http://dx.doi.org/10.3389/fendo.2020.00445
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