P.54Defects in iron-sulphur cluster assembly proteins ISCU and FDX2 cause characteristic mitochondrial myopathy

Iron-sulphur (Fe-S) cluster-containing enzymes are essential for generation of energy for metabolic purposes. The mitochondrial respiratory chain, which includes Fe-S containing enzymes (Complex I-III) and a heme-containing enzyme (Complex IV), may be affected secondary to defects in Fe-S cluster biogenesis. How such defects affect the five enzyme complexes of the respiratory chain at the cellular level in tissues has not been clarified. We have analyzed muscle tissue from four patients with mutations in ISCU encoding mitochondrial Fe-S cluster scaffold protein, ISCU, and four patients with mutations in the FDX2 gene encoding ferredoxin 2. Both proteins are essential for biogenesis of Fe-S clusters and the addition of iron-sulphur proteins to respiratory chain enzymes and heme synthesis. Mutations in ISCU cause mitochondrial myopathy with exercise intolerance and mutations in FDX2 are associated with mitochondrial myopathy and a complex neurological disorder. Muscle histopathology for ISCU cases showed widespread succinate dehydrogenase (SDH) deficiency and iron deposition as well as characteristic regional cytochrome c oxidase (COX) deficiency. FDX2 cases exhibited a similar but less severe pathology with SDH and COX deficiency and iron accumulation overlapping in distinct regions. We further analyzed the expression of Complex I to V (CI-CV) of the respiratory chain in muscle tissue of patients by utilizing antibodies to complex subunits NDUFB8 (CI), SDHB (CII), UQCRC2 (CIII), MTCO1 (CIV), ATPB (CV) and VDAC1 (mitochondrial marker). Complex I-IV subunits showed reduced expression, confined to the same regions as the enzyme-histochemical COX and SDH deficiency. Western blot results were in line with the results from immuno-histochemistry. We conclude that deficiency of both ISCU and FDX2 affects biogenesis and assembly of several respiratory chain complexes resulting in a characteristic regional deficiency of respiratory chain activity.