Mitochondrial Calcium Signaling in Brown Fat Bioenergetics

Abstract

Calcium is a ubiquitous signaling molecule that coordinates biological processes over a wide range of length and timescales. For decades, it has been known that respiring mitochondria can take up large amounts of calcium through a channel known as the uniporter, whose activity has been hypothesized to stimulate oxidative phosphorylation, modulate cytosolic signaling events, and trigger cell death. These hypotheses have historically been untestable, however, due to a lack of tools with which to modulate the activity of the uniporter in intact cells and tissues. Our laboratory pioneered the molecular characterization of the uniporter and reported the composition of the entire uniporter holocomplex in 2013, enabling the channel to be manipulated in vivo for the first time using genetic methods. The identification of the uniporter’s molecular identity has provided an unprecedented opportunity to explore its role in cellular and organismal physiology, both by testing previously generated hypotheses and by using systematic profiling methods. This dissertation describes a series of complementary efforts to delineate the role of the uniporter in brown adipose tissue (BAT), a thermogenic tissue in mammals that is increasingly recognized for its metabolic versatility. Using a combination of cellular and animal models, we systematically examined how ablating uniporter function impacts BAT physiology. We found that, while the uniporter is largely dispensable for brown fat bioenergetics in vivo, it plays a previously unappreciated role in TCA cycle anapleurosis and in lipid metabolism. We additionally found that thermogenesis in BAT is unexpectedly accompanied by the induction of the ATF4-regulated integrated stress response, which we propose to mediate the pleiotropic effects of BAT on systemic metabolism through the circulating hormones FGF21 and GDF15. In addition to helping elucidate the physiological significance of the uniporter, we anticipate that our work will inform future studies of BAT biology, and may point to novel means of modulating BAT activity in the clinic.