USP22 enhances mitochondrial biogenesis via stabilizing MYBBP1A in non-small cell lung cancer.

Mitochondria, central hubs of cellular metabolism, play a pivotal role in tumorigenesis and the regulation of cellular metabolic processes. Cancer cells frequently undergo metabolic reprogramming, characterized by enhanced glycolysis, dysregulated oxidative phosphorylation (OXPHOS), and rewired mitochondrial biogenesis to meet the high bioenergetic and biosynthetic demands of proliferation. In non-small cell lung cancer (NSCLC), these metabolic alterations are hallmark features, yet the upstream regulatory mechanisms governing mitochondrial function remain poorly defined. In this study, we report the novel finding that ubiquitin-specific protease 22 (USP22), a key regulator of protein ubiquitination and transcriptional activity, regulates mitochondrial protein expression and OXPHOS. We further demonstrate that USP22 directly binds to MYB-binding protein 1A (MYBBP1A), thereby modulating the expression of nuclear- and mitochondrial-encoded OXPHOS-related proteins, ultimately promoting mitochondrial biogenesis in cancer cells. To our knowledge, this work provides the first evidence linking USP22 to mitochondrial biogenesis in NSCLC. These findings offer valuable insights into the regulatory network governing mitochondrial metabolism in NSCLC and suggest new avenues for targeting metabolic vulnerabilities in molecular diagnosis and targeted therapies.