Abstract
BackgroundMalignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions. This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. However, the underlying mechanism for mitochondrial dysfunction in glioma is not well elucidated. MTCH2 is a mitochondrial outer membrane protein that regulates mitochondrial metabolism and related cell death. This study aims to clarify the role of MTCH2 in glioma.MethodsBioinformatic analysis from TCGA and CGGA databases were used to investigate the association of MTCH2 with glioma malignancy and clinical significance. The expression of MTCH2 was verified from clinical specimens using real-time PCR and western blots in our cohorts. siRNA-mediated MTCH2 knockdown were used to assess the biological functions of MTCH2 in glioma progression, including cell invasion and temozolomide-induced cell death. Biochemical investigations of mitochondrial and cellular signaling alternations were performed to detect the mechanism by which MTCH2 regulates glioma malignancy.ResultsBioinformatic data from public database and our cohort showed that MTCH2 expression was closely associated with glioma malignancy and poor patient survival. Silencing of MTCH2 expression impaired cell migration/invasion and enhanced temozolomide sensitivity of human glioma cells. Mechanistically, MTCH2 knockdown may increase mitochondrial OXPHOs and thus oxidative damage, decreased migration/invasion pathways, and repressed pro-survival AKT signaling.ConclusionOur work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.
Highlights
Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions
To explore the mechanistic interplay between mitochondrial dysfunction and glioma progression, we focused on mitochondrial carrier homolog 2 (MTCH2), a critical regulator of mitochondrial metabolism and related cell death (Robinson et al 2012; Veresov and Davidovskii 2014)
As a first step to investigate the possible contribution of MTCH2 in gliomagenesis, we analyzed MTCH2 expression profiles across multiple types of human tumors
Summary
Malignant glioma exerts a metabolic shift from oxidative phosphorylation (OXPHOs) to aerobic glycolysis, with suppressed mitochondrial functions This phenomenon offers a proliferation advantage to tumor cells and decrease mitochondria-dependent cell death. Extensive studies established that mitochondrial dysfunction is a prominent mechanism by which glioma cells exert its metabolic shift from oxidative phosphorylation (OXPHOs) to glycolysis, regardless of oxygen availability During this metabolic reprogramming, mitochondrial function in glioma is suppressed through mutations of mitochondrial DNA (Keatley et al 2019), altered metabolic enzyme atlas (Deighton et al 2014; Franceschi et al 2018), and imbalanced morphological dynamics (Xie et al 2015). A number of studies have increased the understanding of mitochondrial dysfunction in glioma cells, the molecular repertoire is still largely unknown
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