Upstream open reading frame-encoded MP31 disrupts the mitochondrial quality control process and inhibits tumorigenesis in glioblastoma.
Neuro Oncol
; 25(11): 1947-1962, 2023 11 02.
Article
em En
| MEDLINE
| ID: mdl-37280112
ABSTRACT
BACKGROUND:
Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy.METHODS:
We used 2-photon fluorescence microscopy, Fluorescence-Activated Cell Sorting, and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima.RESULTS:
MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by reactive oxygen species production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for lactate dehydrogenase B (LDHB) binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes or microglia cells (MG).CONCLUSIONS:
MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in normal human astrocytes and MG. MP31 is a promising candidate for GBM treatment.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glioblastoma
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article