Circulating mitochondrial components and metabolic and inflammatory markers in Charcot-Marie-Tooth type 2B

Charcot-Marie-Tooth type 2B (CMT2B) is a rare inherited neuropathy caused by mutations in the RAB7A gene. Altered mitochondrial dynamics and late endosome trafficking contribute to CMT2B pathophysiology. In this case-control study, we quantified levels of circulating cell-free mtDNA (ccf-mtDNA), mitochondrial proteins secreted within mitochondria-derived vesicles (MDVs), and metabolic and inflammatory markers in biofluids of individuals with CMT2B (n = 5) and healthy controls (n = 4). ccf-mtDNA was quantified in serum by droplet digital PCR. MDVs were purified by immunoprecipitation and analyzed by Western blotting. A panel of 27 inflammatory markers was assayed in serum by multiplex immunoassay. Forty-four amino acids and derivatives were quantified in serum and urine by ultraperformance liquid chromatography/mass spectrometry (UPLC/MS). Fourteen long-chain fatty acids and asymmetric dimethyl arginine (ADMA) were measured in serum by UPLC/MS. Analysis of variance – simultaneous component analysis models were built to explore differences in metabolic and inflammatory markers between cases and controls. Mann–Whitney U test was used to compare ccf-mtDNA levels between groups. Spearman's correlation analysis was applied to explore the relationship between markers of inflammation, endothelial dysfunction, and fatty acid metabolism. CMT2B participants had higher levels of ADMA as well as of interleukin (IL)-1b, IL-8, IL-9, IL-13, eotaxin, and most fatty acids than controls. Serum levels of 1- and 3-methylhistidine, alfa- and beta-aminobutyric acid, asparagine, glycine, threonine, and fibroblast growth factor were lower in CMT2B samples than in controls. No significant differences were observed for ccf-mtDNA levels between groups, while differences in MDV content were identified between participants with CMT2B and controls. Among the metabolic markers, ADMA was the most discriminant biomolecule distinguishing CMT2B participants from controls and showed a positive correlation with some fatty acids. Collectively, these findings suggest that CMT2B may be associated with altered endosomal trafficking and mitochondrial and endothelial dysfunction.