D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Isocitrate dehydrogenase-1 (IDH1) R132 mutations are common in gliomas.
• The physiological impact of these IDH1 mutations in vivo remains unclear.

Purpose of the Study:

• To investigate the in vivo consequences of the IDH1 R132H mutation in a mouse model.
• To elucidate the molecular mechanisms underlying IDH1 mutation-associated pathology.

Main Methods:

• Generation and characterization of brain-specific Idh1 R132H conditional knock-in (KI) mice.
• Analysis of reactive oxygen species (ROS), NADP+/NADPH ratio, D-2-hydroxyglutarate (D2HG) levels, and prolyl-hydroxylation.
• Assessment of hypoxia-inducible transcription factor-1α (Hif1α) activity and collagen maturation.

Main Results:

• Idh1-KI mice exhibited hemorrhage and perinatal lethality.
• Attenuated intracellular ROS and increased NADP+/NADPH ratio were observed in Idh1-KI brain cells.
• Elevated D2HG levels inhibited prolyl-hydroxylation of Hif1α and collagen, leading to ER stress and basement membrane aberrations.

Conclusions:

• The D2HG produced by mutant IDH1 is responsible for hemorrhage, developmental defects, and ER stress via impaired collagen maturation.
• These findings highlight D2HG's role in IDH1-mutated glioma pathogenesis and suggest potential therapeutic targets.