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Updated: Mar 23, 2026
Metabolic Mapping: Quantitative Enzyme Cytochemistry and Histochemistry to Determine the Activity of Dehydrogenases in Cells and Tissues
Published on: May 26, 2018
Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells
Pavithra Viswanath1, Myriam M Chaumeil1, Sabrina M Ronen1
1Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA , USA.
Abstract:
Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have recently been identified as drivers in the development of several tumor types. Most notably, cytosolic IDH1 is mutated in 70-90% of low-grade gliomas and upgraded glioblastomas, and mitochondrial IDH2 is mutated in ~20% of acute myeloid leukemia cases. Wild-type IDH catalyzes the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in the enzyme lead to loss of wild-type enzymatic activity and a neomorphic activity that converts α-KG to 2-hydroxyglutarate (2-HG). In turn, 2-HG, which has been termed an "oncometabolite," inhibits key α-KG-dependent enzymes, resulting in alterations of the cellular epigenetic profile and, subsequently, inhibition of differentiation and initiation of tumorigenesis. In addition, it is now clear that the IDH mutation also induces a broad metabolic reprograming that extends beyond 2-HG production, and this reprograming often differs from what has been previously reported in other cancer types. In this review, we will discuss in detail what is known to date about the metabolic reprograming of mutant IDH cells, and how this reprograming has been investigated using molecular metabolic imaging. We will describe how metabolic imaging has helped shed light on the basic biology of mutant IDH cells, and how this information can be leveraged to identify new therapeutic targets and to develop new clinically translatable imaging methods to detect and monitor mutant IDH tumors in vivo.
Insights
Mutant isocitrate dehydrogenase (IDH) enzymes reprogram cell metabolism, producing 2-hydroxyglutarate (2-HG) oncometabolite. Molecular imaging reveals these metabolic shifts, aiding in identifying new therapeutic targets for IDH-mutant tumors.
Area of Science:
- Oncology
- Metabolic Engineering
- Molecular Imaging
Background:
- Mutations in isocitrate dehydrogenase (IDH) are key drivers in various cancers, including low-grade gliomas and acute myeloid leukemia.
- Mutant IDH enzymes gain a neomorphic activity, converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that disrupts cellular epigenetics and differentiation.
- IDH mutations induce significant metabolic reprogramming beyond 2-HG production, with unique characteristics across different cancer types.
Purpose of the Study:
- To review the metabolic reprogramming in mutant IDH cells.
- To discuss the application of molecular metabolic imaging in understanding these metabolic alterations.
- To explore how metabolic imaging can inform therapeutic strategies and clinical monitoring of IDH-mutant tumors.
Main Methods:
- Review of existing literature on IDH mutations, metabolic reprogramming, and molecular imaging techniques.
- Analysis of how metabolic imaging elucidates the biological consequences of IDH mutations.
- Discussion of the translational potential of metabolic imaging for clinical applications.
Main Results:
- IDH mutations lead to profound metabolic reprogramming, characterized by 2-HG production and other altered metabolic pathways.
- Molecular metabolic imaging provides critical insights into the spatial and temporal metabolic changes within mutant IDH cells.
- Imaging data helps to differentiate mutant IDH tumors and monitor their response to therapy.
Conclusions:
- Metabolic reprogramming is a hallmark of IDH-mutant cancers, driven by both neomorphic 2-HG production and broader metabolic alterations.
- Molecular metabolic imaging is a powerful tool for dissecting the biology of IDH-mutant cells and identifying novel therapeutic vulnerabilities.
- Translational development of metabolic imaging methods holds promise for improved detection, monitoring, and treatment of IDH-mutant tumors.
