Sodium Channels, Mitochondria, and Axonal Degeneration in Peripheral Neuropathy

Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na+/Ca2+ exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition.

TrendsPainful peripheral neuropathy is encountered with increasing frequency in clinical practice but the mechanisms underlying axonal injury are not understood.The development of symptoms in peripheral neuropathy can be length-dependent (initially affecting distal extremities, innervated by the longest fibers) and time-dependent (clinical manifestations usually appear in adulthood). The mechanistic basis of these symptoms has remained enigmatic.Peripheral axons express multiple subtypes of sodium channels, some of which are preferentially expressed in the PNS.The Na+/Ca2+ exchanger in the PNS provides a molecular basis for calcium-importing reverse Na+/Ca2+ exchange in response to Na+ influx that overwhelms homeostatic mechanisms of small-diameter axons; this can lead to axonal degeneration.From an electrical standpoint, the high input impedance (opposition in a circuit) and short-length constant of axons, particularly small-diameter axons, render these especially sensitive to small changes in sodium channel activity.Sustained activity of peripheral Na+ channels has been linked to degeneration of peripheral axons as a result of reverse Na+/Ca2+ exchange, both in normal wild-type and in gain-of-function-mutation sodium channels.Mitochondria are essential for ion homeostasis in axons. The longest nerve fibers (which contain the most mitochondria) are at highest risk of degeneration with aging, and degenerate first. This has provided a basis for length- and age-dependent axonal injury in peripheral neuropathy.