Details

Autor(en) / Beteiligte

• Lu, Zhuo
• Sun, Gui-Feng
• He, Kai-Yi
• Zhang, Zhen
• Han, Xin-Hao
• Qu, Xin-Hui
• Wan, Deng-Feng
• Yao, Dongyuan
• Tou, Fang-Fang
• Han, Xiao-Jian
• Wang, Tao

Titel

Targeted inhibition of branched-chain amino acid metabolism drives apoptosis of glioblastoma by facilitating ubiquitin degradation of Mfn2 and oxidative stress

Ist Teil von

• Biochimica et biophysica acta. Molecular basis of disease, 2024-06, Vol.1870 (5), p.167220-167220, Article 167220

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Glioblastoma is one of the most challenging malignancies with high aggressiveness and invasiveness and its development and progression of glioblastoma highly depends on branched-chain amino acid (BCAA) metabolism. The study aimed to investigate effects of inhibition of BCAA metabolism with cytosolic branched-chain amino acid transaminase (BCATc) Inhibitor 2 on glioblastoma, elucidate its underlying mechanisms, and explore therapeutic potential of targeting BCAA metabolism. The expression of BCATc was upregulated in glioblastoma and BCATc Inhibitor 2 precipitated apoptosis both in vivo and in vitro with the activation of Bax/Bcl2/Caspase-3/Caspase-9 axis. In addition, BCATc Inhibitor 2 promoted K63-linkage ubiquitination of mitofusin 2 (Mfn2), which subsequently caused lysosomal degradation of Mfn2, and then oxidative stress, mitochondrial fission and loss of mitochondrial membrane potential. Furthermore, BCATc Inhibitor 2 treatment resulted in metabolic reprogramming, and significant inhibition of expression of ATP5A, UQCRC2, SDHB and COX II, indicative of suppressed oxidative phosphorylation. Moreover, Mfn2 overexpression or scavenging mitochondria-originated reactive oxygen species (ROS) with mito-TEMPO ameliorated BCATc Inhibitor 2-induced oxidative stress, mitochondrial membrane potential disruption and mitochondrial fission, and abrogated the inhibitory effect of BCATc Inhibitor 2 on glioblastoma cells through PI3K/AKT/mTOR signaling. All of these findings indicate suppression of BCAA metabolism promotes glioblastoma cell apoptosis via disruption of Mfn2-mediated mitochondrial dynamics and inhibition of PI3K/AKT/mTOR pathway, and suggest that BCAA metabolism can be targeted for developing therapeutic agents to treat glioblastoma. [Display omitted] •BCATc Inhibitor 2 induces apoptosis of glioblastoma cells.•The inhibitor promotes ubiquitin degradation of Mfn2 and oxidative stress.•Mfn2 degradation and oxidative stress facilitate mitochondrial fission.•Mitochondrial fission triggers apoptosis through PI3K/AKT/mTOR signaling.