Mitochondria on the move: emerging paradigms of organelle trafficking in tumour plasticity and metastasis

Abstract

There is now a resurgent interest in the role of mitochondria in cancer. Long considered controversial or outright unimportant, mitochondrial biology is now increasingly recognised as an important tumour driver. The underlying mechanisms remain to be fully elucidated. But recent studies have uncovered a complex landscape where reprogramming of mitochondrial homoeostasis, including organelle dynamics, metabolic output, apoptosis control and redox status converge to promote tumour adaptation to an unfavourable microenvironment and inject new traits of aggressive disease. In particular, mechanisms of subcellular mitochondrial trafficking have unexpectedly emerged as central regulators of metastatic competence in disparate tumours. Some of these pathways are druggable, opening fresh therapeutic opportunities for advanced and disseminated disease.

Figure 1

Mitochondrial trafficking to the cortical cytoskeleton. Prostate adenocarcinoma PC3 cells were transfected with control non-targeting siRNA or SNPH-directed siRNA and analysed for mitochondrial repositioning to the cortical cytoskeleton by confocal microscopy. A 3D isosurface rendering of mitochondria was obtained by staining fixed cells with an antibody to mitochondria (green), followed by Alexa Fluor 488-conjugated secondary antibody. DNA (blue) was stained with DAPI.

Figure 2

Mitochondrial reprogramming contributes to tumour plasticity. Stress stimuli of the tumour microenvironment modulate mitochondrial functions in apoptosis inhibition, cell motility and invasion, proliferation, ‘retrograde’ gene expression, metabolic reprogramming and organelle dynamics, including subcellular trafficking. In turn, these mitochondrial functions expand tumour diversity, buffer environmental stress stimuli and introduce new traits of aggressive disease, including drug resistance and metastatic competence.