UCP1 is essential for mitochondrial structural integrity and function in brown adipose tissue

Abstract

With the recent discovery of functional brown adipose tissue (BAT) in humans, there is a renewed interest in harnessing this thermogenic organ for the therapeutic treatment of diabetes and obesity. BAT activation increases energy expenditure and BAT mitochondria, through the actions of uncoupling protein 1 (UCP1), are integral to this energy wasting process. In response to adrenergic stimulation, UCP1 uncouples the proton pumping actions of the electron transport chain from ATP synthesis releasing the stored chemical energy as heat. While this phenomenon has been intensely investigated, surprisingly little is known about how BAT mitochondria distinctively adapt to the expression and activation of UCP1, which makes up a large percentage of BAT mitochondrial proteome. By taking advantage of UCP1‐null animals in combination with bioenergetic profiling and transmission electron microscopy, we provide clear evidence that UCP1 is necessary to maintain mitochondrial structure and function in brown fat. Furthermore, using novel ‘complexomic’ and proteomic profiling we demonstrate that mitochondrial supercomplex formation and stability in BAT requires UCP1. Finally, we show that the loss of UCP1 induces cellular stress, mitochondrial structural alterations and mitochondrial autophagy in an activation dependent manner. Taken together these data suggest that UCP1 is necessary for optimal mitochondrial function and health in brown adipose tissue and call into question any direct mitochondrial mechanism for heat generation in brown fat lacking UCP1.