Acid Sphingomyelinase Downregulation Enhances Mitochondrial Fusion and Promotes Oxidative Metabolism in a Mouse Model of Melanoma

Melanoma is the most severe type of skin cancer. Its unique and heterogeneousmetabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparateconditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and bothare fundamental in tumour progression and metastasis. The malignant phenotype of melanoma is alsoregulated by the expression levels of the enzyme acid sphingomyelinase (A-SMase). By modulatingat transcriptional level A-SMase in the melanoma cell line B16-F1 cells, we assessed the e ect ofenzyme downregulation on mitochondrial dynamics and function. Our results demonstrate thatA-SMase influences mitochondrial morphology by a ecting the expression of mitofusin 1 and OPA1.The enhanced expression of the two mitochondrial fusion proteins, observed when A-SMase isexpressed at low levels, correlates with the increase of mitochondrial function via the stimulationof the genes PGC-1alpha and TFAM, two genes that preside over mitochondrial biogenesis. Thus,the reduction of A-SMase expression, observed in malignant melanomas, may determine theirmetastatic behaviour through the stimulation of mitochondrial fusion, activity and biogenesis,conferring a metabolic advantage to melanoma cells.