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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&gt;A (n=3), m.3460 A&gt;G (n=2), m.3635 G&gt;A (n=1), m.3308 T&gt;G (n=2),  m.3472 T&gt;C (n=1) and 2 patients with earlier unknown substitutions m.3945 C&gt;A and m.14441T&gt;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&lt;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&lt;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.

High resolution respirometry in diagnostic of mitochondrial disorders caused by mitochondrial complex I deficiency