Expanding and validating the biomarkers for mitochondrial diseases

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Mitochondrial diseases are heterogeneous metabolic disorders stemming from genetic defects in mitochondrial or nuclear DNA.
• These conditions often present with significant neurological and muscular symptoms.

Purpose of the Study:

• To investigate the utility of blood biomarkers, including creatine, FGF21, GDF-15, and cell-free circulating mitochondrial DNA (ccf-mtDNA), in patients with mitochondrial diseases.
• To correlate biomarker levels with specific clinical phenotypes and disease activity.

Main Methods:

• Analysis of creatine, FGF21, GDF-15, and ccf-mtDNA in 123 patients with mitochondrial diseases.
• Stratification of biomarker levels based on clinical phenotypes such as MELAS and MERRF.
• Longitudinal assessment of ccf-mtDNA in MELAS patients during acute events.

Main Results:

• All investigated biomarkers (creatine, FGF21, GDF-15, ccf-mtDNA) were elevated in the patient cohort.
• ccf-mtDNA was significantly increased in MELAS patients, while FGF21 and GDF-15 were elevated in MELAS and MERRF.
• Elevated ccf-mtDNA levels correlated with acute events and neurodegeneration progression in MELAS patients.
• FGF21 and GDF-15 confirmed association with mitochondrial translation defects from tRNA mutations.

Conclusions:

• FGF21 and GDF-15 are effective in identifying mitochondrial diseases caused by tRNA gene mutations.
• The novel biomarker ccf-mtDNA is strongly associated with MELAS and its fluctuations may indicate disease activity.
• ccf-mtDNA, FGF21, and GDF-15 show promise as tools for monitoring disease course and evaluating therapy efficacy, particularly during acute phases.