Mitochondria as a central sensor for axonal degenerative stimuli

Axonal degeneration is a major contributor to neuronal dysfunction in many neurological conditions and has additional roles in development. It can be triggered by divergent stimuli including mechanical, metabolic, infectious, toxic, hereditary and inflammatory stresses. Axonal mitochondria are an important convergence point as regulators of bioenergetic metabolism, reactive oxygen species (ROS), Ca²⁺ homeostasis and protease activation. The challenges likely to render axonal mitochondria more vulnerable than their cellular counterparts are reviewed, including axonal transport, replenishing nuclear-encoded proteins and maintenance of quality control, fusion and fission in locations remote from the cell body. The potential for mitochondria to act as a decision node in axon loss is considered, highlighting the need to understand the biology of axonal mitochondria and their contributions to degenerative mechanisms for novel therapeutic strategies.

Introduction

Neuronal soma and axons die by very different mechanisms. Axon degeneration is in many cases an autonomous process that is distinct from classical apoptosis but can be genetically regulated. Conversely, a protein that protects axons, the slow Wallerian degeneration protein (Wld^S), has no known effect on survival of the soma 1, 2. As molecular mechanisms underlying axon survival and degeneration become better understood, it is important to ask what makes them specific for axons.

Many mitochondrial dysfunctions lead to disorders in which axon degeneration is the predominant feature, or a prominent early step (Table 1). Thus, axons may face a greater challenge than neuronal soma or dendrites in maintaining sufficient functioning of mitochondria for survival. Mitochondria, long known to have multiple roles in cell death, differ strikingly between axons and soma. First, their elongated shape, at least in peripheral nerve axons, is specialized for life in a long narrow cylinder [3]. Maintenance of this shape is critical for efficient delivery by axonal transport so that even moderate swelling will block both their own transport and that of many other cargoes (Figure 1). Second, axonal mitochondria are discrete structures, in contrast to the syncytia more typically seen in many cell types. Because of this discontinuity, the delivery of material and exchange with other mitochondria may be more dependent on mechanisms such as fusion and fission. Third, their transport has to be carefully regulated to ensure that mitochondria are focused in the correct regions of the huge axonal compartment [4], which can be several hundred times larger than neuronal soma. In this way, high requirements for adenosine triphosphate (ATP) synthesis and Ca²⁺ buffering can be met.

This review considers the extent to which unique features of axonal mitochondria underlie axon-specific degeneration mechanisms, making them a nodal point for decisions on axon survival. In some cases, axons degenerate through failure to maintain a healthy mitochondrial population at literally ‘arm's length’ from the cell body, whereas in others mitochondria may play a more active role in axon degeneration. The latter process may be much faster, whereas a steady decline in mitochondria quality in axons may take many years and only occur when axonal transport further declines with age.