Isocitrate Dehydrogenase 1 (IDH1) mutations, particularly IDH1R132, are prevalent in various cancers such as Glioblastoma and AML which result in the accumulation of the oncometaboliteD-2-hydroxyglutarate (D-2HG). While mitochondrial dysfunction in IDH1 mutant cells has been extensively studied, the role of peroxisomes remains largely unexplored. Our study investigates the impact of IDH1 mutation on peroxisome morphology, dynamics and function which could potentially reveal novel therapeutic vulnerabilities.
Using confocal and electron microscopy, we observed that IDH1-mutant cells undergo enhanced peroxisome biogenesis, characterized by a marked increase in peroxisome size and number compared to wild-type cells. IDH1 was also found to translocate to peroxisomes, indicating a direct regulatory role that disrupts lipid metabolism. Concurrently, IDH1 mutant cells displayed mitochondria characterized by hyperfused mitochondria with increased size, altered morphology, and dilated cristae, which reverted to wild-type morphology when peroxisomes were depleted by knocking out PEX3. This indicates a functional cross-talk between peroxisomes and mitochondria. Despite increased peroxisome abundance, functional assays revealed substantial impairment of peroxisome function. Treatment with Docosahexaenoic Acid (DHA) failed to induce ferroptosis in mutant cells and isolated peroxisomes showed reduced levels of key peroxisomal enzymes such as catalase These findings suggests that enhanced peroxisome biogenesis and enlargement of peroxisomes in IDH1-mutated cells is a dysfunctional compensatory mechanism rather than enhanced metabolic capacity.
Further analyses utilizing PEX3 knockout cells revealed impaired tumour growth, altered cell morphology, and increased sensitivity to lipid stress, underscoring the essential role of peroxisomes in cancer cell survival. Activation of peroxisome proliferator-activated receptors (PPARγ) effectively modulated peroxisomal abundance, presenting a potential therapeutic strategy, although variable responses were observed among IDH1-mutant patient-derived cells.
In summary, our findings identify peroxisomal dysfunction as a critical vulnerability in IDH1-mutant cancers and highlights peroxisome-targeted interventions as promising avenues for therapeutic development.