Control of mitochondrial transport and localization in neurons

Mitochondria play an essential role in ATP generation, calcium buffering and apoptotic signalling. In neurons, the transport of mitochondria to specific locations where they are needed has emerged as an important process for correct nerve cell function. Recent studies have shed light on the mechanisms that control mitochondrial transport and localization in neurons. We describe the machinery that is important for constitutive transport of mitochondria throughout the cell, and highlight recent advances in our understanding of how signalling pathways can converge on this machinery and allow for rapid activity-dependent control of mitochondrial trafficking and localization. Regulation of mitochondrial trafficking might work in concert with mitochondrial tethering systems to give precise control of mitochondrial delivery and localization to regions of high energy and calcium buffering requirements within neurons.

Introduction

Brain function is an energetically costly business. While the brain is only 2% of the body's weight, it consumes 20% of the body's resting energy production. This high energy consumption is used mainly on reversing the ion influxes underlying synaptic transmission and action potential signalling in neurons [1]. Most brain energy is generated by mitochondria, organelles highly efficient in utilizing oxygen and substrates mainly derived from glucose to produce cellular energy in the form of ATP (Box 1). The large size of many neurons (up to 1 m in humans), which precludes rapid diffusion of ATP from one end of the cell to the other, implies that at the single-cell level energy production must be spatially matched to local energy usage. Thus, mitochondria must be located close to the sites of the ion influxes that generate synaptic and action potentials. Indeed, in neurons, mitochondria can be found enriched at various locations with a high energy demand, including, pre- and post-synaptic domains, the axon initial segment, nodes of Ranvier and growth cones [2]. In addition, patterns of neuronal activity within the brain are constantly changing. Therefore the position of mitochondria in neurons must be controlled on rapid timescales to match changes in synaptic input. Mitochondria also sequester and buffer cytoplasmic calcium and thus their localization plays a role in local regulation of intracellular calcium dynamics with important implications for neural signalling, the formation of new synapses and for changes in synapse strength. During development and in the adult, mitochondrial trafficking and anchoring are therefore likely to be necessary regulatory mechanisms that allow for the rapid redistribution and recruitment of mitochondria to localized areas with increased energy or calcium buffering requirements.