The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species
Background. Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Hindawi Limited
2018-01-01
|
Series: | Oxidative Medicine and Cellular Longevity |
Online Access: | http://dx.doi.org/10.1155/2018/7514383 |
id |
doaj-8b7c98383ebe45988cf45ac3a22b9c36 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hung-Yu Lin Shao-Wen Weng Yen-Hsiang Chang Yu-Jih Su Chih-Min Chang Chia-Jen Tsai Feng-Chih Shen Jiin-Haur Chuang Tsu-Kung Lin Chia-Wei Liou Ching-Yi Lin Pei-Wen Wang |
spellingShingle |
Hung-Yu Lin Shao-Wen Weng Yen-Hsiang Chang Yu-Jih Su Chih-Min Chang Chia-Jen Tsai Feng-Chih Shen Jiin-Haur Chuang Tsu-Kung Lin Chia-Wei Liou Ching-Yi Lin Pei-Wen Wang The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species Oxidative Medicine and Cellular Longevity |
author_facet |
Hung-Yu Lin Shao-Wen Weng Yen-Hsiang Chang Yu-Jih Su Chih-Min Chang Chia-Jen Tsai Feng-Chih Shen Jiin-Haur Chuang Tsu-Kung Lin Chia-Wei Liou Ching-Yi Lin Pei-Wen Wang |
author_sort |
Hung-Yu Lin |
title |
The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species |
title_short |
The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species |
title_full |
The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species |
title_fullStr |
The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species |
title_full_unstemmed |
The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen Species |
title_sort |
causal role of mitochondrial dynamics in regulating insulin resistance in diabetes: link through mitochondrial reactive oxygen species |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2018-01-01 |
description |
Background. Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D-susceptible haplogroup B4 remains unanswered. Methods. To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS-AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi-1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. Results. Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1-AKT pathway and GLUT translocation stimulated by insulin were improved. On the contrary, suppression of mitochondrial network caused a reduction of the IRS1-AKT pathway and GLUT translocation stimulated by insulin. Pharmacologically inhibiting mitochondrial fission by the Drp1 inhibitor, mdivi-1, also rescued mitochondrial network, reduced mtROS, and improved insulin signaling of diabetes-susceptible cybrid cells. Conclusion. Our results discovered the causal role of mtDYN proteins in regulating IR resulted from diabetes-susceptible mitochondrial haplogroup. The existence of a bidirectional interaction between mtDYN and mtROS plays an important role. Direct intervention to reverse profission in mtDYN provides a novel therapeutic strategy for IR and T2D. |
url |
http://dx.doi.org/10.1155/2018/7514383 |
work_keys_str_mv |
AT hungyulin thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT shaowenweng thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT yenhsiangchang thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT yujihsu thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chihminchang thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chiajentsai thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT fengchihshen thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT jiinhaurchuang thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT tsukunglin thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chiaweiliou thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chingyilin thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT peiwenwang thecausalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT hungyulin causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT shaowenweng causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT yenhsiangchang causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT yujihsu causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chihminchang causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chiajentsai causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT fengchihshen causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT jiinhaurchuang causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT tsukunglin causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chiaweiliou causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT chingyilin causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies AT peiwenwang causalroleofmitochondrialdynamicsinregulatinginsulinresistanceindiabeteslinkthroughmitochondrialreactiveoxygenspecies |
_version_ |
1716819229794107392 |
spelling |
doaj-8b7c98383ebe45988cf45ac3a22b9c362020-11-24T20:43:39ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942018-01-01201810.1155/2018/75143837514383The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link through Mitochondrial Reactive Oxygen SpeciesHung-Yu Lin0Shao-Wen Weng1Yen-Hsiang Chang2Yu-Jih Su3Chih-Min Chang4Chia-Jen Tsai5Feng-Chih Shen6Jiin-Haur Chuang7Tsu-Kung Lin8Chia-Wei Liou9Ching-Yi Lin10Pei-Wen Wang11Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanDepartment of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, TaiwanBackground. Mitochondrial dynamics (mtDYN) has been proposed as a bridge between mitochondrial dysfunction and insulin resistance (IR), which is involved in the pathogenesis of type 2 diabetes (T2D). Our previous study has identified that mitochondrial DNA (mtDNA) haplogroup B4 is a T2D-susceptible genotype. Using transmitochondrial cybrid model, we have confirmed that haplogroup B4 contributes to cellular IR as well as a profission mtDYN, which can be reversed by antioxidant treatment. However, the causal relationship between mtDYN and cellular IR pertaining to T2D-susceptible haplogroup B4 remains unanswered. Methods. To dissect the mechanisms between mtDYN and IR, knockdown or overexpression of MFN1, MFN2, DRP1, and FIS1 was performed using cybrid B4. We then examined the mitochondrial network and mitochondrial oxidative stress (mtROS) as well as insulin signaling IRS-AKT pathway and glucose transporters (GLUT) translocation to plasma membrane stimulated by insulin. We employed Drp1 inhibitor, mdivi-1, to interfere with endogenous expression of fission to validate the pharmacological effects on IR. Results. Overexpression of MFN1 or MFN2 increased mitochondrial network and reduced mtROS, while knockdown had an opposing effect. In contrast, overexpression of DRP1 or FIS1 decreased mitochondrial network and increased mtROS, while knockdown had an opposing effect. Concomitant with the enhanced mitochondrial network, activation of the IRS1-AKT pathway and GLUT translocation stimulated by insulin were improved. On the contrary, suppression of mitochondrial network caused a reduction of the IRS1-AKT pathway and GLUT translocation stimulated by insulin. Pharmacologically inhibiting mitochondrial fission by the Drp1 inhibitor, mdivi-1, also rescued mitochondrial network, reduced mtROS, and improved insulin signaling of diabetes-susceptible cybrid cells. Conclusion. Our results discovered the causal role of mtDYN proteins in regulating IR resulted from diabetes-susceptible mitochondrial haplogroup. The existence of a bidirectional interaction between mtDYN and mtROS plays an important role. Direct intervention to reverse profission in mtDYN provides a novel therapeutic strategy for IR and T2D.http://dx.doi.org/10.1155/2018/7514383 |