Figure xA Inflammatory demyelination and amplification factors

The geometry of the neuron–axon unit presents a substantial challenge for efficient distribution of mitochondria and ATP production within axons, which can reach a metre in length in humans. Unlike the continuous mitochondrial reticulum seen in most cells, myelinated AGN 192403 have two populations of mitochondria. Most axonal mitochondria are located at stationary mitochondrial sites distributed along the entire axonal length. Individual stationary sites can contain several long (1–4 μm) mitochondria and are deemed to be the major generators of axonal ATP, while the smaller motile mitochondria facilitate turnover and redistribution of stationary mitochondrial sites via fusion and fission.90 and 91 Axons are extremely susceptible to mitochondrial dysfunction (figure 3). Mutations in mitochondrial DNA and nuclear DNA encoding mitochondrial proteins and mitochondrial molecular motors, which are tolerated in small cells, cause degeneration in axons. Demyelination has a substantial effect on axonal mitochondria and renders the demyelinated axon susceptible to chronic environmental conditions that eventually result in axonal transection. Here, we discuss how reduced ATP production, increased reactive oxygen species production, and altered Ca2+ buffering by mitochondria in demyelinated axons drive progressive disability in patients with multiple sclerosis.