GRPEL2 Knockdown Exerts Redox Regulation in Glioblastoma

Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The GrpE-like 2 homolog (GRPEL2) plays a crucial role in regulating mitochondrial protein import and redox homeostasis. However, the role of GRPEL2 in human glioblastoma has yet to be clarified. In this study, we investigated the function of GRPEL2 in glioma. Based on bioinformatics analyses from the Cancer Gene Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we inferred that GRPEL2 expression positively correlates with WHO tumor grade (p < 0.001), IDH mutation status (p < 0.001), oligodendroglial differentiation (p < 0.001), and overall survival (p < 0.001) in glioma datasets. Functional validation in LN229 and GBM8401 GBM cells showed that GRPEL2 knockdown efficiently inhibited cellular proliferation. Moreover, GRPEL2 suppression induced cell cycle arrest at the sub-G1 phase. Furthermore, GRPEL2 silencing decreased intracellular reactive oxygen species (ROS) without impending mitochondria membrane potential. The cellular oxidative respiration measured with a Seahorse XFp analyzer exhibited a reduction of the oxygen consumption rate (OCR) in GBM cells by siGRPEL2, which subsequently enhanced autophagy and senescence in glioblastoma cells. Taken together, GRPEL2 is a novel redox regulator of mitochondria bioenergetics and a potential target for treating GBM in the future.

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Faculty Opinions recommendation of α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726410495.793533852 ◽

2017 ◽

Author(s):

Joseph Jankovic

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Import ◽

Mitochondrial Protein ◽

Mitochondrial Protein Import

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Faculty Opinions recommendation of Regulation of mitochondrial protein import by cytosolic kinases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8927956.9483055 ◽

2011 ◽

Author(s):

Peter Rehling

Keyword(s):

Protein Import ◽

Mitochondrial Protein ◽

Mitochondrial Protein Import

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MicroRNA-490-5P Targets CCND1 to Suppress Cellular Proliferation in Glioma Cells and Tissue Through Cell Cycle Arrest

Current Neurovascular Research ◽

10.2174/1567202615666180813130143 ◽

2018 ◽

Vol 15 (3) ◽

pp. 246-255 ◽

Cited By ~ 4

Author(s):

Long Zhao ◽

Xiaoping Tang ◽

Renguo Luo ◽

Jie Duan ◽

Yuanchuan Wang ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cellular Proliferation ◽

Glioma Cells ◽

Cycle Arrest

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Role of an energized inner membrane in mitochondrial protein import. Delta psi drives the movement of presequences.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)55235-2 ◽

1991 ◽

Vol 266 (27) ◽

pp. 18051-18057

Author(s):

J. Martin ◽

K. Mahlke ◽

N. Pfanner

Keyword(s):

Protein Import ◽

Mitochondrial Protein ◽

Mitochondrial Protein Import ◽

Inner Membrane

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Characterization of Mmp37p, aSaccharomyces cerevisiaeMitochondrial Matrix Protein with a Role in Mitochondrial Protein Import

Molecular Biology of the Cell ◽

10.1091/mbc.e06-04-0366 ◽

2006 ◽

Vol 17 (9) ◽

pp. 4051-4062 ◽

Cited By ~ 47

Author(s):

Michelle R. Gallas ◽

Mary K. Dienhart ◽

Rosemary A. Stuart ◽

Roy M. Long

Keyword(s):

Matrix Protein ◽

Protein Import ◽

Mitochondrial Protein ◽

Temperature Sensitive ◽

Inner Membrane ◽

Mitochondrial Inner Membrane ◽

Close Proximity ◽

The Matrix ◽

Targeting Signal

Many mitochondrial proteins are encoded by nuclear genes and after translation in the cytoplasm are imported via translocases in the outer and inner membranes, the TOM and TIM complexes, respectively. Here, we report the characterization of the mitochondrial protein, Mmp37p (YGR046w) and demonstrate its involvement in the process of protein import into mitochondria. Haploid cells deleted of MMP37 are viable but display a temperature-sensitive growth phenotype and are inviable in the absence of mitochondrial DNA. Mmp37p is located in the mitochondrial matrix where it is peripherally associated with the inner membrane. We show that Mmp37p has a role in the translocation of proteins across the mitochondrial inner membrane via the TIM23-PAM complex and further demonstrate that substrates containing a tightly folded domain in close proximity to their mitochondrial targeting sequences display a particular dependency on Mmp37p for mitochondrial import. Prior unfolding of the preprotein, or extension of the region between the targeting signal and the tightly folded domain, relieves their dependency for Mmp37p. Furthermore, evidence is presented to show that Mmp37 may affect the assembly state of the TIM23 complex. On the basis of these findings, we hypothesize that the presence of Mmp37p enhances the early stages of the TIM23 matrix import pathway to ensure engagement of incoming preproteins with the mtHsp70p/PAM complex, a step that is necessary to drive the unfolding and complete translocation of the preprotein into the matrix.

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