Abstract
Mitochondrial disorders are genetically and clinically heterogeneous, mainly affecting high energy-demanding organs due to impaired oxidative phosphorylation (OXPHOS). Currently, effective treatments for OXPHOS defects, with complex I deficiency being the most prevalent, are not available. Yet, clinical practice has shown that some complex I deficient patients benefit from a high-fat or ketogenic diet, but it is unclear how these therapeutic diets influence mitochondrial function and more importantly, which complex I patients could benefit from such treatment. Dietary studies in a complex I deficient patient with exercise intolerance showed increased muscle endurance on a high-fat diet compared to a high-carbohydrate diet. We performed whole-exome sequencing to characterize the genetic defect. A pathogenic homozygous p.G212V missense mutation was identified in the TMEM126B gene, encoding an early assembly factor of complex I. A complementation study in fibroblasts confirmed that the p.G212V mutation caused the complex I deficiency. The mechanism turned out to be an incomplete assembly of the peripheral arm of complex I, leading to a decrease in the amount of mature complex I. The patient clinically improved on a high-fat diet, which was supported by the 25% increase in maximal OXPHOS capacity in TMEM126B defective fibroblast by the saturated fatty acid palmitic acid, whereas oleic acid did not have any effect in those fibroblasts. Fibroblasts of other patients with a characterized complex I gene defect were tested in the same way. Patient fibroblasts with complex I defects in NDUFS7 and NDUFAF5 responded to palmitic acid, whereas ACAD9, NDUFA12, and NDUFV2 defects were non-responding. Although the data are too limited to draw a definite conclusion on the mechanism, there is a tendency that protein defects involved in early assembly complexes, improve with palmitic acid, whereas proteins defects involved in late assembly, do not. Our data show at a clinical and biochemical level that a high fat diet can be beneficial for complex I patients and that our cell line assay will be an easy tool for the selection of patients, who might potentially benefit from this therapeutic diet.
Highlights
Mitochondrial disorders are genetically and clinically heterogeneous metabolic disorders with a prevalence of ∼1 in 5,000 in the general population (Skladal et al, 2003; Gorman et al, 2015)
A skin biopsy was taken from the TMEM126B patient and dermal fibroblast were isolated in a similar manner as previously executed for the five other patients with complex I deficiency (NDUFS7, NDUFAF5, ACAD9, NDUFA12, NDUFV2 defective fibroblasts), who were all biochemically and genetically diagnosed at the Maastricht University Medical Centre (MUMC+)
Primary dermal fibroblasts from the patient were obtained by taking a 3–5 mm punch biopsy from the arm, which was cut into 18 smaller pieces and 3 biopsy pieces were transferred to each gelatin pre-coated 6-well containing Dulbecco’s Modified Eagle Medium (DMEM, 25 mM glucose) supplemented with 20% fetal bovine serum (FBS)
Summary
Mitochondrial disorders are genetically and clinically heterogeneous metabolic disorders with a prevalence of ∼1 in 5,000 in the general population (Skladal et al, 2003; Gorman et al, 2015). For the treatment of mitochondrial myopathies due to complex I deficiency the therapeutic use of high-fat diets has been recommended, as supplementation of fatty acids via direct triacylglycerol infusion was shown to significantly improve exercise endurance in some patients (Roef et al, 2002) The latter observation was explained by an increase in mitochondrial beta-oxidation, which results in relatively higher FADH2:NADH++H+ ratios than the carbohydrate driven tricarboxylic acid cycle, thereby enabling bypassing of the complex I defect (Roef et al, 2002; Paoli et al, 2014; Steriade et al, 2014). This mechanism cannot by itself explain why only some of the complex I deficient patients respond to high-fat treatment, suggesting that these treatments influence the OXPHOS system, at least in part, in a gene- or protein-specific manner (Hughes et al, 2014; Frey et al, 2017)
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