Inhibition of Mitochondrial Carrier Homolog 2 (MTCH2) Suppresses Tumor Invasion and Enhances Sensitivity to Temozolomide in Malignant Glioma

Abstract

Background: 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. 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.Methods: Bioinformatic 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.Results: Bioinformatic 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.Conclusion: Our work establishes the relationship between MTCH2 expression and glioma malignancy, and provides a potential target for future interventions.

APOC1 promotes the progression of osteosarcoma by binding to MTCH2

“…MTCH2 is a 33 kDa protein localized in the mitochondrial outer membrane (43,44). Studies imply that MTCH2 is involved in the pathogenesis of numerous types of tumors (13,45,46). For example, CRISPR screening has identified MTCH2 as key for the proliferation and viability of leukemia cells and MTCH2 deletion decreases proliferation and promotes the differentiation of acute myeloid leukemia cells (45).…”

“…For example, CRISPR screening has identified MTCH2 as key for the proliferation and viability of leukemia cells and MTCH2 deletion decreases proliferation and promotes the differentiation of acute myeloid leukemia cells (45). Emerging evidence has shown that MTCH2 knockdown impedes invasion and migration of glioma cells and renders cells susceptible to temozolomide-triggered apoptosis (13). MTCH2 is significantly downregulated in ErbB2-driven breast cancer, the induction of which attenuates tumorigenicity and causes cell cycle arrest in breast cancer (46).…”

“…As an important regulator of mitochondrial metabolism and cell death, MTCH2 expression is upregulated in clinical osteosarcoma samples (11,12). MTCH2 is a suppressor of oxidative phosphorylation (OXPHOS), and the metabolic switch from OXPHOS to glycolysis is a hallmark of osteosarcoma (13,14).…”