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

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

  • Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167220. doi: 10.1016/j.bbadis.2024.167220.
Zhuo Lu 1,  Gui-Feng Sun 2,  Kai-Yi He 3,  Zhen Zhang 4,  Xin-Hao Han 2,  Xin-Hui Qu 5,  Deng-Feng Wan 6,  Dongyuan Yao 7,  Fang-Fang Tou 2,  Xiao-Jian Han 8,  Tao Wang 9
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, PR China.
  • 2 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China.
  • 3 Department of Pharmacology, School of Pharmaceutical Science, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, PR China.
  • 4 Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China.
  • 5 The Second Department of Neurology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China.
  • 6 Department of Neurosurgery, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China.
  • 7 Neurological Institute of Jiangxi Province, Department of Neurology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China.
  • 8 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China; Department of Pharmacology, School of Pharmaceutical Science, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, PR China; Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China. Electronic address: hanxiaojian@hotmail.com.
  • 9 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, PR China. Electronic address: wangtaoalepellis@gmail.com.
PMID: 38718847 DOI: 10.1016/j.bbadis.2024.167220
Abstract

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.

Keywords

Apoptosis; BCATc Inhibitor 2; Glioblastoma; Mfn2; Oxidative stress; PI3K/AKT/mTOR signaling.

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