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. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: CNS Drugs. 2019 Dec;33(12):1155–1166. doi: 10.1007/s40263-019-00684-6

Figure 3: IDH1 R132H impacts the status of the Bcl-2 family of proteins.

Figure 3:

The IDH1 mutation confers a neomorphic enzymatic activity, resulting in the production of 2-Hydroxyglutarate (2-HG). 2-HG inhibits the ETC (electron transport chain) through impacting the electron flow to molecular oxygen by interference with cytochrome-c oxidase and in part by inhibition of complex V. This results in lower ATP levels, followed by reduction of protein synthesis and lower levels of protein with a short-half life, such as the anti-apoptotic Bcl-2 family member Mcl-1. Lower levels of Mcl-1 shift the survival dependency towards Bcl-xL and/or Bcl-2, creating a mitochondrial Bcl-2 family related vulnerability, which can be executed by the BH3-mimetic, ABT263, resulting in BAX/BAK activation and permeabilization of the outer mitochondrial membrane. In addition, interference with ETC itself can impact mitochondrial membrane potential prime mitochondrial for BAX/BAK mediated apoptosis. Proapoptotic Bcl-2 family members (Puma, BIM, Noxa) either directly or indirectly activate BAX/BAK to facilitate apoptosis.