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IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state
Author(s) -
Wang Yuan,
Agarwal Ekta,
Bertolini Irene,
Ghosh Jagadish C.,
Seo Jae Ho,
Altieri Dario C.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901366r
Subject(s) - idh2 , biology , mitochondrion , bioenergetics , microbiology and biotechnology , citric acid cycle , cancer cell , warburg effect , isocitrate dehydrogenase , tumor microenvironment , tumor hypoxia , cancer research , cancer , biochemistry , idh1 , metabolism , enzyme , genetics , medicine , tumor cells , mutation , gene , radiation therapy
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‐1α 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., Agarwal, E., Bertolini, I., Ghosh, J. C., Seo, J. H., Altieri, D. C. IDH2 reprograms mitochondrial dynamics in cancer through a HIF‐1α‐regulated pseudohypoxic state. FASEB J. 33, 13398–13411 (2019). www.fasebj.org