In conclusion, our study contributed the first exploratory results on the potential of a new biomarker for mitochondrial diseases, the ccf-mtDNA, which seems to hallmark phenotypes with very active neurodegeneration such as MELAS, and further confirmed the validity of FGF21 and GDF-15 as useful biomarkers, mostly sensing mitochondrial myopathy. Here, FGF21 is linked to mitochondrial disease.