Peripheral neuropathy, a group of over 100 debilitating disorders that affect millions of people in the United States, may be triggered by the degeneration of mitochondria in neuronal axons far away from the brain.
Peipheral neuropathies involve damage to neurons that transmit signals from the central nervous system to the rest of the body, and sensory information from the body to the brain. Symptoms include muscle weakness, numbness, paralysis and difficulty in swallowing or breathing. However, the exact causes for neural degeneration are not completely clear.
Now, researchers Ahmet Hoke, Helmar Lehmann, Weiran Chen, Jasenka Borzan and Joseph Mankowski of Hopkins think they have found part of the answer.
Hoke’s and his colleagues’ work relies on the fact that neuropathy occurs more often and earlier in older and taller patients. In addition, patients suffering from various diseases such as HIV or diabetes are at higher risk for neuropathy.
Taking note of these trends, the research teams began to explore the role mitochondria may play in the degenerative process.
Many diseases can contribute or exacerbate neuropathies; HIV is a common trigger. By studying tissue samples from HIV-positive patients with and without neuropathy at the time of their deaths and healthy patients with no neuropathy, Hoke and his colleagues hoped to better understand why neural degeneration occurs.
Through examination of tissue samples from nerves taken at locations close to the spinal cord and farther away from it, such as in the feet, Hoke’s team has been able to establish that mitochondria found at increasing distances from the spinal cord possess increasing numbers of mutations in their mitochondrial DNA. These mutations include defects that can affect how mitochondria work.
To take the work a step farther, the team has also examined whether mutated mitochondria are truly less effective at providing the cell with energy and keeping it healthy.
In order to study live mitochondria though, the team has sought a monkey model of HIV neuropathy.
Mitochondrial extracts from these experimental animals have revealed results which seem to agree with Hoke’s human work: mitochondria found farther from the root of the spinal cord were found to be less functional and to produce less energy while also producing increasing levels of faulty proteins and damaging molecules called free radicals.
In the course of disease or aging, mitochondrial DNA may become damaged. Because mitochondria have such a long path to travel from the cell body of neurons to their distal axonal regions, accumulation of damaged mitochondria is more prevalent farther from the cell body.
This phenomenon explains why taller people, who have longer nerves, and older people, who have had more time to accumulate mutations, tend to suffer more from neuropathies.
These findings also explain why neuropathies start in the feet and then move up the legs and begin affecting the arms — the long neurons which have to reach all the way to the feet are
much more susceptible to the mitochondrial defects seen in Hoke’s studies.
The scientists’ finding agrees with a long history of studies on peripheral neuropathy. However, the study is among the first to directly tie mitochondrial function to increasing damage and the disease state.
“Long ends of peripheral nerves are very unique in their mitochondria because it takes almost two to three years for a mitochondria made in the neuronal cell body in the lumbar region to reach to the feet,” Hoke wrote in an email to The News-Letter, “They may accumulate deletion mutations and be partially dysfunctional compared to mitochondria closer to the cell body.”
Though the present results are specific to HIV-related neuropathy, Hoke believes that a similar mechanism may be at work in other diseases such as diabetes.
The ultimate goal for researchers is to assess the state of a patient’s mitochondria with the hope that treatment could be administered to salvage function and/or prevent further degeneration.
“I think if we can figure out a way to improve mitochondrial function, we may be able to prevent or delay degeneration of distal axons in many peripheral neuropathies,” Hoke wrote.
Furthermore, improving that mitochondrial function can have a dramatic impact on neuropathy in a disease state, according to Hoke.
“One of our overall hypotheses to explain why some people with diabetes develop neuropathy and others do not is that a given person’s mitochondrial DNA deletion/mutation burden may predispose them to neuropathy i.e. if they start with higher levels of mtDNA deletions/mutations their distal axons are more likely to be susceptible to the nerve damaging effects of diabetes. This is still a hypothesis and needs to be tested,” he wrote.
In any case, Hoke and his colleagues’ work have shown not only the increased toll paid by mitochondria under stressful aging and diseased conditions, but also the effects of that damage which may manifest themselves as painful and debilitating neuropathies.
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