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Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy.

Lim TK, Rone MB, Lee S, Antel JP, Zhang J - Mol Pain (2015)

Bottom Line: Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis.Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling.Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

View Article: PubMed Central - PubMed

Affiliation: Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. tony.lim@mail.mcgill.ca.

ABSTRACT

Background: Mitochondrial dysfunction is observed in various neuropathic pain phenotypes, such as chemotherapy induced neuropathy, diabetic neuropathy, HIV-associated neuropathy, and in Charcot-Marie-Tooth neuropathy. To investigate whether mitochondrial dysfunction is present in trauma-induced painful mononeuropathy, a time-course of mitochondrial function and bioenergetics was characterized in the mouse partial sciatic nerve ligation model.

Results: Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis. Increased metabolic needs of the nerve are concomitant with bioenergetic and mitochondrial dysfunction. Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling. Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

Conclusion: Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues.

No MeSH data available.


Related in: MedlinePlus

The bioenergetic profile of mouse sciatic nerves can be assessed by Seahorse metabolic assay. Sciatic nerves from mice were isolated and cut into small 1 mm hemi-segments. Tissue from a 3 mm long segment of nerve was placed into a single well. a Oxygen consumption rate was measured, and the oxygen consumption rate in response to oligomycin, FCCP, and antimycin A with rotenone was determined. This allowed ex vivo measurement of oxygen consumption specific to total cellular respiration, mitochondrial respiration, mitochondrial ATP production, mitochondrial proton leak, mitochondrial maximal respiration, mitochondrial spare respiratory capacity, and non-mitochondrial respiration. b Extracellular acidification rate can also be measured by this method. Ex vivo measurement of the extracellular acidification rate corresponding to total extracellular acidification, glycolysis, glycolytic capacity, glycolytic reserve, and non-glycolytic acidification can be measured following administration of oligomycin and 2-deoxyglucose to the tissue culture medium
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Fig1: The bioenergetic profile of mouse sciatic nerves can be assessed by Seahorse metabolic assay. Sciatic nerves from mice were isolated and cut into small 1 mm hemi-segments. Tissue from a 3 mm long segment of nerve was placed into a single well. a Oxygen consumption rate was measured, and the oxygen consumption rate in response to oligomycin, FCCP, and antimycin A with rotenone was determined. This allowed ex vivo measurement of oxygen consumption specific to total cellular respiration, mitochondrial respiration, mitochondrial ATP production, mitochondrial proton leak, mitochondrial maximal respiration, mitochondrial spare respiratory capacity, and non-mitochondrial respiration. b Extracellular acidification rate can also be measured by this method. Ex vivo measurement of the extracellular acidification rate corresponding to total extracellular acidification, glycolysis, glycolytic capacity, glycolytic reserve, and non-glycolytic acidification can be measured following administration of oligomycin and 2-deoxyglucose to the tissue culture medium

Mentions: A method to examine the bioenergetics profile of mice nerves was developed. Oxygen consumption and extracellular acidification rates from mouse sciatic nerves ex vivo were measured with the Seahorse XF extracellular flux analyzer. Oligomycin, FCCP, and antimycin A with rotenone was used to measure oxygen consumption linked to: total respiration, ATP-linked respiration, proton leak, non-mitochondrial respiration, maximal mitochondrial respiration, and the spare respiratory capacity (Fig. 1a). Oligomycin and 2-deoxy-d-glucose were used to measure extracellular acidification linked to: glycolysis, non-glycolygic acidification, glycolytic capacity, and glycolytic reserve (Fig. 1b).Fig. 1


Mitochondrial and bioenergetic dysfunction in trauma-induced painful peripheral neuropathy.

Lim TK, Rone MB, Lee S, Antel JP, Zhang J - Mol Pain (2015)

The bioenergetic profile of mouse sciatic nerves can be assessed by Seahorse metabolic assay. Sciatic nerves from mice were isolated and cut into small 1 mm hemi-segments. Tissue from a 3 mm long segment of nerve was placed into a single well. a Oxygen consumption rate was measured, and the oxygen consumption rate in response to oligomycin, FCCP, and antimycin A with rotenone was determined. This allowed ex vivo measurement of oxygen consumption specific to total cellular respiration, mitochondrial respiration, mitochondrial ATP production, mitochondrial proton leak, mitochondrial maximal respiration, mitochondrial spare respiratory capacity, and non-mitochondrial respiration. b Extracellular acidification rate can also be measured by this method. Ex vivo measurement of the extracellular acidification rate corresponding to total extracellular acidification, glycolysis, glycolytic capacity, glycolytic reserve, and non-glycolytic acidification can be measured following administration of oligomycin and 2-deoxyglucose to the tissue culture medium
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4574230&req=5

Fig1: The bioenergetic profile of mouse sciatic nerves can be assessed by Seahorse metabolic assay. Sciatic nerves from mice were isolated and cut into small 1 mm hemi-segments. Tissue from a 3 mm long segment of nerve was placed into a single well. a Oxygen consumption rate was measured, and the oxygen consumption rate in response to oligomycin, FCCP, and antimycin A with rotenone was determined. This allowed ex vivo measurement of oxygen consumption specific to total cellular respiration, mitochondrial respiration, mitochondrial ATP production, mitochondrial proton leak, mitochondrial maximal respiration, mitochondrial spare respiratory capacity, and non-mitochondrial respiration. b Extracellular acidification rate can also be measured by this method. Ex vivo measurement of the extracellular acidification rate corresponding to total extracellular acidification, glycolysis, glycolytic capacity, glycolytic reserve, and non-glycolytic acidification can be measured following administration of oligomycin and 2-deoxyglucose to the tissue culture medium
Mentions: A method to examine the bioenergetics profile of mice nerves was developed. Oxygen consumption and extracellular acidification rates from mouse sciatic nerves ex vivo were measured with the Seahorse XF extracellular flux analyzer. Oligomycin, FCCP, and antimycin A with rotenone was used to measure oxygen consumption linked to: total respiration, ATP-linked respiration, proton leak, non-mitochondrial respiration, maximal mitochondrial respiration, and the spare respiratory capacity (Fig. 1a). Oligomycin and 2-deoxy-d-glucose were used to measure extracellular acidification linked to: glycolysis, non-glycolygic acidification, glycolytic capacity, and glycolytic reserve (Fig. 1b).Fig. 1

Bottom Line: Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis.Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling.Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

View Article: PubMed Central - PubMed

Affiliation: Neurology and Neurosurgery, McGill University, Montreal, QC, H3A 2B4, Canada. tony.lim@mail.mcgill.ca.

ABSTRACT

Background: Mitochondrial dysfunction is observed in various neuropathic pain phenotypes, such as chemotherapy induced neuropathy, diabetic neuropathy, HIV-associated neuropathy, and in Charcot-Marie-Tooth neuropathy. To investigate whether mitochondrial dysfunction is present in trauma-induced painful mononeuropathy, a time-course of mitochondrial function and bioenergetics was characterized in the mouse partial sciatic nerve ligation model.

Results: Traumatic nerve injury induces increased metabolic indices of the nerve, resulting in increased oxygen consumption and increased glycolysis. Increased metabolic needs of the nerve are concomitant with bioenergetic and mitochondrial dysfunction. Mitochondrial dysfunction is characterized by reduced ATP synthase activity, reduced electron transport chain activity, and increased futile proton cycling. Bioenergetic dysfunction is characterized by reduced glycolytic reserve, reduced glycolytic capacity, and increased non-glycolytic acidification.

Conclusion: Traumatic peripheral nerve injury induces persistent mitochondrial and bioenergetic dysfunction which implies that pharmacological agents which seek to normalize mitochondrial and bioenergetic dysfunction could be expected to be beneficial for pain treatment. Increases in both glycolytic acidification and non-glycolytic acidification suggest that pH sensitive drugs which preferentially act on acidic tissue will have the ability to preferential act on injured nerves without affecting healthy tissues.

No MeSH data available.


Related in: MedlinePlus