CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance

Jan Lumibao, Payton Haak, Vladimir Kolossov, Jee-Wei Chen, Jeremy Stutchman, Alejandra Ruiz, Mayandi Sivaguru, Jann Sarkaria, Brendan Harley, Andrew Steelman, H. Rex Gaskins

Research output: Contribution to journalArticlepeer-review


Glioblastoma (GBM) is the most common and malignant primary brain tumor affecting adults and remains incurable. The mitochondrial coiled‑coil‑helix‑coiled‑coil‑helix domain‑containing protein 2 (CHCHD2) has been demonstrated to mediate mitochondrial respiration, nuclear gene expression and cell migration; however, evidence of this in GBM is lacking. In the present study, it was hypothesized that CHCHD2 may play a functional role in U87 GBM cells expressing the constitutively active epidermal growth factor receptor variant III (EGFRvIII). The amplification of the CHCHD2 gene was found to be associated with a decreased patient overall and progression‑free survival. The CHCHD2 mRNA levels were increased in high‑vs. low‑grade glioma, IDH‑wt GBMs, and in tumor vs. non‑tumor tissue. Additionally, CHCHD2 protein expression was greatest in invasive, EGFRvIII‑expressing patient‑derived samples. The CRISPR‑Cas9‑mediated knockout of CHCHD2 in EGFRvIII‑expressing U87 cells resulted in an altered mitochondrial respiration and glutathione status, in decreased cell growth and invasion under both normoxic and hypoxic conditions, and in an enhanced sensitivity to cytotoxic agents. CHCHD2 was distributed in both the mitochondria and nuclei of U87 and U87vIII cells, and the U87vIII cells exhibited a greater nuclear expression of CHCHD2 compared to isogenic U87 cells. Incubation under hypoxic conditions, serum starvation and the reductive unfolding of CHCHD2 induced the nuclear accumulation of CHCHD2 in both cell lines. Collectively, the findings of the present study indicate that CHCHD2 mediates a variety of GBM characteristics, and highlights mitonuclear retrograde signaling as a pathway of interest in GBM cell biology.
Original languageEnglish (US)
Article number117
JournalInternational journal of oncology
Issue number5
StatePublished - Nov 2023


  • coiled‑coil‑helix‑coiled‑ coil‑helix domain‑containing protein 2
  • epidermal growth factor receptor variant III
  • glioblastoma
  • mitochondria

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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