Abstract
The BCL2 family of proteins regulate apoptosis by controlling mitochondrial outer membrane permeability. However, the effects on mitochondrial structure and bioenergetics have also been reported. Here we comprehensively characterized the effects of BCL2 and BCL(X)L on cellular energetics in MCF7 breast cancer cells using time-lapse confocal single-cell imaging and mitochondrial and cytosolic FRET reporters. We found that BCL2 and BCL(X)L increase the metabolic robustness of MCF7 cells, and that this was associated with increased mitochondrial NAD(P)H and ATP levels. Experiments with the F1F0 synthase inhibitor oligomycin demonstrated that BCL2 and in particular BCL(X)L, while not affecting ATP synthase activity, more efficiently coupled the mitochondrial proton motive force with ATP production. This metabolic advantage was associated with an increased resistance to nutrient deprivation and enhanced clonogenic survival in response to metabolic stress, in the absence of profound effects on cell death. Our data suggest that a primary function of BCL(X)L and BCL2 overexpression in tumor cells is to increase their resistance to metabolic stress in the tumor microenvironment, independent of cell death signaling.
Highlights
BCL2 family members regulate the intrinsic apoptosis pathway by controlling the process of mitochondrial outer membrane permeabilisation (MOMP) [1]
A pool of BCL(X)L has been found to localise in the inner mitochondrial membrane (IMM) and to interact with F1F0 ATP synthase, increasing its enzymatic activity and stabilizing mitochondrial membrane potential (ΔΨm) [9, 10]
We explored whether BCL2 and BCL(X)L were acting on F1F0 ATP synthase to enhance mitochondrial energetics of breast cancer cells, by performing an oligomycin titration
Summary
BCL2 family members regulate the intrinsic apoptosis pathway by controlling the process of mitochondrial outer membrane permeabilisation (MOMP) [1]. Apart from this function, BCL2 proteins regulate mitochondrial fusion and fission [2,3,4,5]. This process is important for mitochondrial quality control, and regulates mitochondrial bioenergetics [6]. BCL2 proteins may control mitochondrial metabolism directly. BCL2 and BAX regulate the activity of the mitochondrial adenine nucleotide translocator [7]. A similar function was attributed to a truncated form of MCL1 that localizes to the matrix [11]
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