Dual role of the mitochondrial protein frataxin in astrocytic tumors

Abstract

The mitochondrial protein frataxin (FXN) is known to be involved in mitochondrial iron homeostasis and iron-sulfur cluster biogenesis. It is discussed to modulate function of the electron transport chain and production of reactive oxygen species (ROS). FXN loss in neurons and heart muscle cells causes an autosomal-dominant mitochondrial disorder, Friedreich's ataxia. Recently, tumor induction after targeted FXN deletion in liver and reversal of the tumorigenic phenotype of colonic carcinoma cells following FXN overexpression were described in the literature, suggesting a tumor suppressor function. We hypothesized that a partial reversal of the malignant phenotype of glioma cells should occur after FXN transfection, if the mitochondrial protein has tumor suppressor functions in these brain tumors. In astrocytic brain tumors and tumor cell lines, we observed reduced FXN levels compared with non-neoplastic astrocytes. Mitochondrial content (citrate synthase activity) was not significantly altered in U87MG glioblastoma cells stably overexpressing FXN (U87-FXN). Surprisingly, U87-FXN cells exhibited increased cytoplasmic ROS levels, although mitochondrial ROS release was attenuated by FXN, as expected. Higher cytoplasmic ROS levels corresponded to reduced activities of glutathione peroxidase and catalase, and lower glutathione content. The defect of antioxidative capacity resulted in increased susceptibility of U87-FXN cells against oxidative stress induced by H 2 O 2 or buthionine sulfoximine. These characteristics may explain a higher sensitivity toward staurosporine and alkylating drugs, at least in part. On the other hand, U87-FXN cells exhibited enhanced growth rates in vitro under growth factor-restricted and hypoxic conditions and in vivo using tumor xenografts in nude mice. These data contrast to a general tumor suppressor function of FXN but suggest a dual, pro-proliferative but chemosensitizing role in astrocytic tumors.

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

“…However, there is little reference in the literature to the expression and function of Fxn in astrocytes (Kirches et al, 2011;Franco et al, 2012). Therefore, our observation of significantly less Fxn protein and mRNA transcripts in human astrocytes several days after in vitro knockdown is consistent with our data from neuron-like cells (Palomo et al, 2011) and those from other cell types (Santos et al, 2001;Lu & Cortopassi, 2007;Napoli et al, 2007;Zanella et al, 2008).…”

An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia

“…Importantly, the deeper investigation of the crosstalk between FXN and GPX4 could increase our knowledge about FXN in modulating intracellular redox homeostasis. Some works corroborate this assumption as an increase in the antioxidant response was found upon FXN overexpression in tumour cell lines, arguing that this protein could also act as a tumour suppressor [73,74].…”

Canine intracranial gliomas: Relationship between magnetic resonance imaging criteria and tumor type and grade

“…The reason why astrocytomas might be T1W-hyper-intense is unclear; iron and manganese levels in astrocytomas have not been well studied and lipids are not present histopathologically. Hepcidin (Hänninen et al, 2009), which functions in iron export, and frataxin (Kirches et al, 2011), which is involved in mitochondrial iron homeostasis, have been found to be reduced in tissues or cell lines of human astrocytomas, but the radiological implications of such aberrations have not been investigated.…”