Cellular energy expenditure and the importance of uncoupling1

Abstract

Just as total body energy expenditure in animals can be broken down into that which supports resting energy metabolism, work, growth, and so on, cellular energy expenditure can similarly be subclassified. The objective in this review is to examine the metabolic origins of cellular energy expenditure, with an emphasis on mitochondrial uncoupling. Mitochondrial uncoupling refers to the dissociation of energy substrate oxidation from the mitochondrial synthesis of ATP. Uncoupling can occur during states of high energy expenditure, as in brown adipose tissue (BAT), or during states of metabolic rest, as in many other tissues. In BAT, uncoupling protein 1 (UCP1) activity can cause very high rates of energy expenditure for the purpose of thermogenesis (heat production). While mitochondrial uncoupling also occurs in other cells of the body, it is of greatest importance to fractional rates of energy expenditure during periods of relative metabolic rest. The latter form of uncoupling is referred to as mitochondrial proton leak and is estimated to account for roughly 20 to 25% of the resting metabolic rate. Leak activity is correlated with thyroid hormone status; scales roughly in proportion with the well-known differences in mass-specific basal metabolic rate in mammals of different body size, and is related to differences in basal metabolic rate between ectothermic and endothermic animals. Proposed functions for mitochondrial uncoupling through proton leak include thermogenesis, energy balance, control of oxidative phosphorylation efficiency, and protection from reactive oxygen species. The mechanisms of mitochondrial proton leak are not well understood; the recently identified uncoupling proteins may play some role, but one or more of these proteins may have other physiological functions, such as fatty acid translocation.