Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase.

Jo, Seung-Hee; Son, Mi-Kyung; Koh, Ho‐Jin; Lee, Su‐Min; Song, In‐Hwan; Kim, Yong-Ou; Lee, Young-Sup; Jeong, Kyu‐Shik; Kim, Won; Park, Jeen‐Woo; Song, Byoung Joon; Huh, Tae‐Lin

doi:10.1016/s0021-9258(19)30242-x

Cited by 5 publications

(5 citation statements)

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“…Considerable effort has been devoted to characterize mutant IDH2 as a validated therapeutic target in gliomas and acute leukemias (13,14), but the function of WT IDH2 in cancer has remained controversial. The data presented here uncovered a new role for IDH2 as an endogenous inhibitor of tumor cell migration and invasion, buffering ROS signals (22) and suppressing mitochondrial dynamics (12). This conclusion is at variance with a proposed oncogenic role of IDH2 in lung cancer (18), but it is in line with other data pointing to an antitumorigenic function of this pathway (20), including inhibition of cell migration and invasion (27) and modulation of matrix metalloproteinase activity (28).…”

Section: Discussionsupporting

confidence: 83%

“…Contrary to what is expected for a tumor suppressor, IDH2-deficient mice exhibit reduced tumor growth (17), and changes in IDH2 levels have been variously linked to tumor growth (18) or tumor suppression (19,20). This pathway may involve ROS unbalance (21), as IDH2 serves a key antioxidant function in mitochondria by supplying NADPH for glutathione reductase (22) and the regeneration of the thioredoxin system (23).…”

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confidence: 99%

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IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state

et al. 2019

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The role of mitochondria in cancer continues to be debated and paradoxically implicated in opposing functions in tumor growth and tumor suppression. To understand this dichotomy, we explored the function of mitochondrial isocitrate dehydrogenase (IDH)2, a tricarboxylic acid cycle enzyme mutated in subsets of acute leukemias and gliomas, in cancer. Silencing of IDH2 in prostate cancer cells impaired oxidative bioenergetics, elevated reactive oxygen species (ROS) production, and promoted exaggerated mitochondrial dynamics. This was associated with increased subcellular mitochondrial trafficking, turnover of membrane focal adhesion complexes, and enhanced tumor cell migration and invasion, without changes in cell cycle progression. Mechanistically, loss of IDH2 caused ROS-dependent stabilization of hypoxia-inducible factor-1a in normoxia, which was required for increased mitochondrial trafficking and tumor cell movements. Therefore, IDH2 is a dual regulator of cancer bioenergetics and tumor cell motility. This pathway may reprogram mitochondrial dynamics to differentially adjust energy production or promote tumor cell invasion in response to microenvironment conditions.-Wang, Y.,

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Section: Discussionsupporting

confidence: 83%

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confidence: 99%

IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state

et al. 2019

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“…IDH2 is the mitochondrial NADPH‐dependent enzyme that catalyzes the conversion of isocitrate to α‐ketoglutarate by oxidative decarboxylation. NADPH produced in this process is a fundamental cofactor of GSH‐associated mitochondrial antioxidant defense systems, including GSH peroxidase and GSH reductase [40], which maintain the availability of GSH in a reduced state in the mitochondria. Therefore, IDH2 is crucial for GSH turnover and defense against ROS.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells

et al. 2021

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Sunitinib (Sun), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, is the standard first‐line treatment against advanced clear cell renal cell carcinoma (RCC), but resistance to therapy is inevitable. Reactive oxygen species production is associated with sensitivity to chemotherapy, but the underlying mechanisms are not completely understood. Here, we investigated the mechanisms contributing to Sun resistance using the RCC cell lines ACHN and 786‐O. We report that Sun‐resistant cells exhibited reduced apoptosis, increased cell viability, increased reactive oxygen species production and disrupted mitochondrial function. Furthermore, chronic Sun treatment resulted in an up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels. Knockdown of Sirt5/IDH2 impaired mitochondrial function and partially attenuated Sun resistance. Finally, up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promoted protein stability. In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity.

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“…IDH1 and IDH2 are nicotinamide adenine dinucleotide phosphate (NADP)-dependent, and each one functions as homodimers; whereas IDH3 is nicotinamide adenine dinucleotide (NAD)-dependent and is composed by three different subunits; thus resulting in the production of the reduced form of NADP (NADPH) by IDH1/2, or NADH by IDH3 in addition to the AKG synthesis [ 82 ]. It is well known that NADPH is a substrate for antioxidant defense, used for glutathione regeneration and thioredoxin activity [ 83 , 84 , 85 ]. In addition, the administration of AKG also has been reported to function directly as an antioxidant [ 86 , 87 , 88 ], as mentioned below.…”

Section: Alpha-ketoglutaratementioning

confidence: 99%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.

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Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase.

Cited by 5 publications

References 0 publications

IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state

IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state

Dysregulation of the Sirt5/IDH2 axis contributes to sunitinib resistance in human renal cancer cells

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

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