USP34 modulates mitochondrial function in triple-negative breast cancer cells through the eIf3m/MTCH2 axis.

Triple-negative breast cancer (TNBC) represents a particularly aggressive form of breast tumors. Mitochondrial dysfunction represses the proliferation of TNBC cells. Ubiquitin-specific proteases 34 (USP34) has been predicted to be abnormally overexpressed in TNBC. This research examined the role of USP34 in the mitochondrial function modulation of TNBC. Herein, cell proliferation was evaluated by the 5-ethynyl-2'-deoxyuridine assay. Mitochondrial membrane potential was detected employing the JC-1 assay. Mitochondrial superoxide was measured utilizing MitoSOX Red assay. Mito‑Tracker Red CMXRos staining was selected to monitor mitochondrial network structure. The relationship among USP34, eukaryotic translation initiation factor 3 m (eIF3m), and mitochondrial carrier homolog 2 (MTCH2) was validated by co-immunoprecipitation, GST-pull down, RNA immunoprecipitation and RNA-pull down analysis. We found that USP34 silencing inhibited cell proliferation by inducing mitochondrial dysfunction in TNBC cells. USP34 maintained the stability of the eIF3m protein through deubiquitination. Overexpression of eIF3m countered the mitochondrial dysfunction induced by USP34 silencing. Furthermore, eIF3m upregulated the MTCH2 level by directly binding to its 5'UTR region. MTCH2 overexpression reversed the damaging effect of eIF3m silencing on mitochondrial function. Collectively, USP34 maintained the stability of eIF3m protein through deubiquitination; the upregulated eIF3m bound to the 5'UTR of MTCH2 mRNA to promote MTCH2 expression, thereby maintaining mitochondrial function and promoting the malignant progression of TNBC.