Compartmentalization of Bioenergetic Substrate Delivery in Intact Cells

Abstract

The intracellular production and transport of energetic substrate adenosine triphosphate (ATP) produced by mitochondria is dependent on multiple factors. These include local metabolic demand, mitochondrial motility and intracellular location, mitochondrial intermembrane potential, bioenergy substrate diffusion within the cell cytosol, and energy transport to the cell nucleus, which itself does not contain any mitochondria. Herein, we demonstrate via cell-based experiment and scaling argument that intracellular bioenergy transport is readily compartmentalized into perinuclear and peripheral regions of the cell. We draw on direct fluorescence-based measurement of quantum dot tracking, high-resolution respirometry, mitochondrial dynamics, and intermembrane potential to assess intracellular quantum dot diffusion to define the intracellular milieu for small molecule transport, and chemical perturbations which challenge cells by altering bioenergetics states. We identify a heterogeneous environment for intracellular bioenergy transport, with a dominant feature being present: the intracellular bioenergy distribution in response to pharmacologically induced cell challenge is determined to be preservation of perinuclear mitochondrial ATP-linked respiration in order to preserve, maintain, or otherwise support bioenergy delivery to meet the metabolic requirements of the cell nucleus whereas there is a decrement in bioenergetic capacity in the cell periphery. This dynamic effect of motile intracellular bioenergy production yields efficient transport of ATP in the maintenance of cellular health.