[Frontiers in Bioscience 1, d91-116, July 1, 1996]


Peter J. Hollenbeck

Dept. of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.

Received 05/30/96; Accepted 06/10/96; On-line 07/01/96


Within the constellation of organelle types that move in the axon, mitochondria hold a special place because of both their functions and their motility properties. Their essential functions are the aerobic production of ATP and the regulation of intracellular calcium levels, and their unusual pattern of motility includes regulated, saltatory bidirectional movement and prolonged stationary phases. The theme of this review is that organelle motility and organelle function are closely related, and its purpose is to assess what is known about the relationship between mitochondrial motility and function, and to propose hypotheses informed by recent research about how these two properties are coordinated in the axon.

The past decade has seen remarkable advances in our knowledge of the biochemical and biophysical basis of general organelle transport in axons. Workers in this field have at their disposal diverse methods for studying the movement of organelles: metabolic labeling and monitoring of organelle proteins in mature nerve (1); direct microscopic observation of organelles in a variety of neurons grown in culture (e.g., 24); and in vitro systems ranging from nearly intact axoplasm devoid of its axolemma (5, 6) to simple reconstituted systems comprising no more than putative molecular motors, cytoskeletal filaments, and ATP (7). As a result, we have at present a burgeoning number of motor proteins, some of which may serve to generate force for the movement of organelles along the cytoskeletal tracks formed by microtubules (MTs) or actin microfilaments (MFs) (8-10). In addition, recent work has offered candidates for motor protein receptors on the surface of organelles and regulatory factors for transport (11-13), and some insight into posttranslational modifications of motor proteins that may serve to modulate transport (14-21).

However, we still know relatively little about how the axon responds to physiological changes by transporting specific organelle types to the regions where they are required at the appropriate time. This is because only recently has much attention been paid to the profound differences in transport of different kinds of organelles, even within the same region of the axon. Small vesicles, endosomes, autophagic vacuoles, pinosomes, and mitochondria each display different patterns of transport in the axon (22), suggesting that there exist essential organelle-specific differences in motility and its regulation.

That the appropriate regulation of the transport and distribution of mitochondria is an essential element of the life of a neuron is underscored by recent studies of diverse neurodegenerative diseases (23). Three common themes in the pathology of many such diseases -- oxidative damage to neurons (24), excitotoxicity and the failure of calcium homeostasis (25), and metabolic inadequacy in the distal axon (26) -- all come together at the mitochondrion and its functional capacities. However important it may be to gain a clear understanding of how the life cycle of mitochondria is related to that of the neuron as a whole, it will only be possible if we analyze the axonal transport of this unique organelle separately from that of other organelle types which have very different functions.

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