Abstract
Melanoma is the most severe type of skin cancer. Its unique and heterogeneous metabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparate conditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and both are fundamental in tumour progression and metastasis. The malignant phenotype of melanoma is also regulated by the expression levels of the enzyme acid sphingomyelinase (A-SMase). By modulating at transcriptional level A-SMase in the melanoma cell line B16-F1 cells, we assessed the effect of enzyme downregulation on mitochondrial dynamics and function. Our results demonstrate that A-SMase influences mitochondrial morphology by affecting the expression of mitofusin 1 and OPA1. The enhanced expression of the two mitochondrial fusion proteins, observed when A-SMase is expressed at low levels, correlates with the increase of mitochondrial function via the stimulation of 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 their metastatic behaviour through the stimulation of mitochondrial fusion, activity and biogenesis, conferring a metabolic advantage to melanoma cells.
Highlights
Whereas the majority of malignant tumours rely on enhanced glycolysis for energy supply [1], melanoma, the most aggressive form of skin cancer, has a unique metabolism, orchestrated by its environment and specific signalling mutations [2,3,4,5]
To assess the relationship between acid sphingomyelinase (A-SMase) expression and mitochondrial morphology, we used transmission electron microscopy to analyse the shape of the mitochondria of explanted murine melanoma allografts
By ultrastructural analysis we found that control tumours presented mostly rounded and small mitochondria, while elongated and more tubular mitochondria accumulated in B16-W6_pSIL10 melanomas (Figure 1A)
Summary
Whereas the majority of malignant tumours rely on enhanced glycolysis for energy supply (i.e., the Warburg effect) [1], melanoma, the most aggressive form of skin cancer, has a unique metabolism, orchestrated by its environment and specific signalling mutations [2,3,4,5]. Increasing evidence indicates that mitochondrial respiration contributes to transformation, development of drug resistance and metastasis in melanomas, defining a pleiotropic role of mitochondria in tumourigenesis [9,10,11,12,13]. In normal and cancer cells, mitochondria exist in a dynamic network resulting from the interplay between fission and fusion events [14,15], governed by nutrient levels and energy demands [16]. In fragmented mitochondria, when fission exceeds fusion, oxidative metabolism is reduced and glycolytic intermediates are preserved for a highly activated glycolysis to provide fuel for cell proliferation [17,18]. When mitochondrial fusion prevails, the outcome is an extension in the mitochondrial network, an event that provides specific metabolic advantages to cells under high energy needs, such as metastatic cells. The primary players in mitochondrial morphology are mitofusin and mitofusin (Mfn, Mfn2), and optic atrophy 1 (OPA1), which are essential for outer and inner mitochondrial membrane fusion, respectively, and dynamin-related protein 1 (Drp1), which is essential for the process of fission [14,15,19,23]
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