IDH2 deficiency impairs mitochondrial function in endothelial cells and endothelium-dependent vasomotor function

Park, Jung-Bum; Nagar, Harsha; Choi, Si Hwan; Jung, Sungyup; Kim, Hyun Woo; Kang, Shin Kwang; Lee, Jun Wan; Lee, Jin Hyup; Park, Jeen‐Woo; Irani, Kaikobad; Song, Hee‐Jung; Kim, Cuk-Seong

doi:10.1016/j.freeradbiomed.2016.02.017

Cited by 33 publications

(25 citation statements)

References 31 publications

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“…Among these, mitochondria serve not only as energy‐producing machines but also as signalling hubs that orchestrate and activate a set of signals such as those associated with redox, metabolism, autophagy, proliferation, inflammation, and intrinsic death pathways . As expected, a series of studies have demonstrated the pathogenic role of mitochondria in the development of endothelial injury …”

Section: Introductionmentioning

confidence: 75%

“…10 As expected, a series of studies have demonstrated the pathogenic role of mitochondria in the development of endothelial injury. [11][12][13][14] Mitochondria-associated membranes (MAMs) are one of the most prominent regulators in mitochondrial biology. 15 The proximity of the endoplasmic reticulum (ER) to mitochondria enables formation of connections between the two organelles.…”

Section: Introductionmentioning

confidence: 99%

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Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Yang

et al. 2019

J of Cellular Biochemistry

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Mitochondrial dysfunction plays a principal role in hypoxia‐induced endothelial injury, which is involved in hypoxic pulmonary hypertension and ischemic cardiovascular diseases. Recent studies have identified mitochondria‐associated membranes (MAMs) that modulate mitochondrial function under a variety of pathophysiological conditions such as high‐fat diet‐mediated insulin resistance, hypoxia reoxygenation‐induced myocardial death, and hypoxia‐evoked vascular smooth muscle cell proliferation. However, the role of MAMs in hypoxia‐induced endothelial injury remains unclear. To explore this further, human umbilical vein endothelial cells and human pulmonary artery endothelial cells were exposed to hypoxia (1% O2) for 24 hours. An increase in MAM formation was uncovered by immunoblotting and immunofluorescence. Then, we performed small interfering RNA transfection targeted to MAM constitutive proteins and explored the biological effects. Knockdown of MAM constitutive proteins attenuated hypoxia‐induced elevation of mitochondrial Ca2+ and repressed mitochondrial impairment, leading to an increase in mitochondrial membrane potential and ATP production and a decline in reactive oxygen species. Then, we found that MAM disruption mitigated cell apoptosis and promoted cell survival. Next, other protective effects, such as those pertaining to the repression of inflammatory response and the promotion of NO synthesis, were investigated. With the disruption of MAMs under hypoxia, inflammatory molecule expression was repressed, and the eNOS‐NO pathway was enhanced. This study demonstrates that the disruption of MAMs might be of therapeutic value for treating endothelial injury under hypoxia, suggesting a novel strategy for preventing hypoxic pulmonary hypertension and ischemic injuries.

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Section: Introductionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Yang

et al. 2019

J of Cellular Biochemistry

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“…IDH2 serves both reductive and oxidative functions ranging from glutathione reduction to NAD(P)H generation depending on cellular requirements. 12,[45][46][47][48][49] To study these changes, we analyzed membrane potential and respiration in both in vivo and in vitro models. Our data indicate that mitochondria membrane potential was increased in Idh2 transfected cells compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Kolb

Corridon²,

Zhang

et al. 2018

JASN

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Ischemic preconditioning confers organ-wide protection against subsequent ischemic stress. A substantial body of evidence underscores the importance of mitochondria adaptation as a critical component of cell protection from ischemia. To identify changes in mitochondria protein expression in response to ischemic preconditioning, we isolated mitochondria from ischemic preconditioned kidneys and sham-treated kidneys as a basis for comparison. The proteomic screen identified highly upregulated proteins, including NADP +-dependent isocitrate dehydrogenase 2 (IDH2), and we confirmed the ability of this protein to confer cellular protection from injury in murine S3 proximal tubule cells subjected to hypoxia. To further evaluate the role of IDH2 in cell protection, we performed detailed analysis of the effects of Idh2 gene delivery on kidney susceptibility to ischemia-reperfusion injury. Gene delivery of IDH2 before injury attenuated the injury-induced rise in serum creatinine (P,0.05) observed in controls and increased the mitochondria membrane potential (P,0.05), maximal respiratory capacity (P,0.05), and intracellular ATP levels (P,0.05) above those in controls. This communication shows that gene delivery of Idh2 can confer organ-wide protection against subsequent ischemiareperfusion injury and mimics ischemic preconditioning.

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“…Silencing of mitochondrial IDH2 in ECs increases the levels of ROS, the oxidized/ reduced glutathione ratio, while impairing oxygen consumption and increasing mitochondrial fragmentation, likely because mitochondrial DNA and proteins are exquisitely sensitive to oxidative stress [71]. IDH2 knockdown also decreases eNOS activation and lowers NO levels in ECs [71]. While this study shows the role of IDH2 in redox homeostasis in healthy ECs, its relevance in atherosclerotic conditions remains to be determined.…”

Section: Metabolic Pathways Regulating Redox Homeostasis In Ecsmentioning

confidence: 74%

“…G6PD overexpression in ECs restores the redox balance in conditions of high glucose [69,70]. Silencing of mitochondrial IDH2 in ECs increases the levels of ROS, the oxidized/ reduced glutathione ratio, while impairing oxygen consumption and increasing mitochondrial fragmentation, likely because mitochondrial DNA and proteins are exquisitely sensitive to oxidative stress [71]. IDH2 knockdown also decreases eNOS activation and lowers NO levels in ECs [71].…”

Section: Metabolic Pathways Regulating Redox Homeostasis In Ecsmentioning

confidence: 99%

Endothelial cell metabolism: A novel player in atherosclerosis? Basic principles and therapeutic opportunities

et al. 2016

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IDH2 deficiency impairs mitochondrial function in endothelial cells and endothelium-dependent vasomotor function

Cited by 33 publications

References 31 publications

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

Exogenous Gene Transmission of Isocitrate Dehydrogenase 2 Mimics Ischemic Preconditioning Protection

Endothelial cell metabolism: A novel player in atherosclerosis? Basic principles and therapeutic opportunities

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