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In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth\/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA\u00a0was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes\/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Key messages<\/jats:title>\n<jats:p><jats:italic>\u2022 FGF21\/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes.<\/jats:italic><\/jats:p>\n<jats:p><jats:italic>\u2022 The novel ccf-mtDNA is associated with MELAS and increases during acute events.<\/jats:italic><\/jats:p>\n<jats:p><jats:italic>\u2022 Creatine only discriminates severe mitochondrial patients.<\/jats:italic><\/jats:p>\n<jats:p><jats:italic>\u2022 FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.<\/jats:italic><\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s00109-020-01967-y","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T16:02:18Z","timestamp":1598457738000},"page":"1467-1478","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Expanding and validating the biomarkers for mitochondrial diseases"],"prefix":"10.1007","volume":"98","author":[{"given":"Alessandra","family":"Maresca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Del Dotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Romagnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"La Morgia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Di Vito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariantonietta","family":"Capristo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Lucia","family":"Valentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-6404","authenticated-orcid":false,"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the ER-MITO Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"1967_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1042\/EBC20170097","volume":"62","author":"V Carelli","year":"2018","unstructured":"Carelli V, La Morgia C (2018) Clinical syndromes associated with mtDNA mutations: where we stand after 30 years. 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All procedures were performed according to the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors reviewed and approved this manuscript for publication.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}