Krylova 2017 Biomed Khim

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Krylova TD, Tsygankova PG, Itkis YS, Sheremet NL, Nevinitsyna TA, Mikhaylova SV, Zakharova EY (2017) High resolution respirometry in diagnostic of mitochondrial disorders caused by mitochondrial complex I deficiency. Biomed Khim 63:327-33.

» PMID: 28862604

Krylova TD, Tsygankova PG, Itkis YS, Sheremet NL, Nevinitsyna TA, Mikhaylova SV, Zakharova EY (2017) Biomed Khim

Abstract: Complex I (CI) deficiency is one of the most common defects in the OXPHOS system; it represents more than 30% cases of mitochondrial diseases. The group is characterized by clinical and genetic heterogeneity and comprise several nosological forms. The most prevalent phenotypes for CI are LHON and Leigh syndrome. In this study we have analyzed skin fibroblasts from 11 patients with mutations in mtDNA, which cause LHON or Leigh-like phenotypes: m.11778 G>A (n=3), m.3460 A>G (n=2), m.3635 G>A (n=1), m.3308 T>G (n=2), m.3472 T>C (n=1) and 2 patients with earlier unknown substitutions m.3945 C>A and m.14441T>C. High-resolution respirometry (HRR) on the Oxygraph-2k instrument ("Oroboros corp.", Austria) was performed for complex analysis of the mitochondrial respiratory function in intact and permeabilized fibroblasts of patients and healthy controls. Flux control rations in intact cells R/E, (R-L)/E (p<0.05) were raised compared to the control. Rates of R, E, L normalized on the CS were statistically varied between patients and controls. In permeabilized fibroblasts we observed differences in CII/E, Rot/E, R/CII, CI/CII (p<0.05) between groups. These data highlight the dysfunction of the OXPHOS system and particularly CI. Increased citrate synthase level and decreased CI/CII ratio indicate compensatory metabolic response to respiratory chain dysfunction. Our results show applicability of HRR in revealing the biochemical abnormalities of complex I in fibroblasts of patients with LHON and Leigh-like syndrome. We also suggest HRR to be a useful method for inspection of other mutations causing complex I deficiency.

Keywords: LHON, Leigh syndrome, Complex I deficiency, High-resolution respirometry Bioblast editor: Kandolf G O2k-Network Lab: RU Moscow Itkis YS


Labels: MiParea: Respiration, mtDNA;mt-genetics, mt-Medicine  Pathology: Neurodegenerative  Stress:Mitochondrial disease  Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell, Fibroblast  Preparation: Intact cells, Permeabilized cells 


Coupling state: ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

Labels, 2018-01, noPDF