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Review
. 2021 Jan;124(1):115-123.
doi: 10.1038/s41416-020-01159-y. Epub 2020 Nov 18.

Mitochondrial oxidative phosphorylation in cutaneous melanoma

Prakrit R Kumar  1 , Jamie A Moore  1 , Kristian M Bowles  1   2 , Stuart A Rushworth  3 , Marc D Moncrieff  4   5
Affiliations
Review

Mitochondrial oxidative phosphorylation in cutaneous melanoma

Prakrit R Kumar et al. Br J Cancer. 2021 Jan.

Abstract

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Metabolism in melanoma.
a The smooth co-operation of OXPHOS and glycolysis in the two spatially distinct melanoma cell populations (melanoma cells in the centre that use glycolysis versus melanoma cells in periphery that use OXPHOS mainly for energy production) promotes melanoma initiation, growth and metastasis of melanoma through metabolic symbiosis, whereby the waste products from glycolysis are used to feed into the TCA cycle for OXPHOS in melanoma cells in the periphery. b Mesenchymal stromal cells (MSCs) migrate from the bone marrow and liver towards the melanoma, where they are then manipulated by tumour cells to produce lactate and other macromolecules via glycolysis, for use by melanoma cells that mainly use OXPHOS in the peripheral part of the tumour (Reverse Warburg).
Fig. 2
Fig. 2. Mechanisms of mtDNA transfer.
a Tunnelling nanotubules (TNTs), b microvesicles and c gap junctions, as well as other plausible mechanisms that require further research, such as d cell fusion and e direct mtDNA secretion into extracellular media.
See this image and copyright information in PMC

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