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The following is a summary of “Enhanced mitochondrial biogenesis facilitates the development of cutaneous squamous cell carcinoma” published in the May 2025 issue of Cancer Letters by Wang et al.

Mitochondrial dysfunction has long been regarded as a hallmark of tumor progression, traditionally linked to malignant transformation through metabolic reprogramming. However, recent studies have presented contrasting views, suggesting that functional mitochondria are essential for tumor growth. Despite these emerging perspectives, the precise role of mitochondria in cutaneous squamous cell carcinoma (cSCC) remains insufficiently characterized. In this study, researchers observed a marked increase in mitochondrial abundance and function during cSCC progression, highlighting the critical involvement of mitochondria in tumor development. Additionally, the study group identified retinoic acid receptor response 1 (RARRES1), a protein significantly downregulated in human cSCC specimens, as a key regulator of mitochondrial homeostasis. 

Mechanistically, RARRES1 translocates into mitochondria and facilitates the degradation of mitochondrial transcription factor A (TFAM) by binding to the ATP-dependent Lon protease (LONP1), thereby restricting mitochondrial biogenesis. The suppression of RARRES1 unleashes TFAM activity, enhancing mitochondrial biogenesis and consequently promoting cutaneous squamous cell carcinoma progression. These findings establish a mechanistic link between RARRES1 downregulation and mitochondrial expansion in cSCC, further emphasizing the indispensable role of mitochondrial regulation in tumor growth. Moreover, targeting the RARRES1-LONP1/TFAM axis presents a promising therapeutic avenue for inhibiting cSCC progression by disrupting mitochondrial homeostasis. This study unveils a novel regulatory network governing mitochondrial function and underscores mitochondria as a pivotal determinant in cSCC pathophysiology, positioning the RARRES1-LONP1/TFAM axis as a potential target for future clinical applications.

Source: sciencedirect.com/science/article/pii/S0304383525001879