Estudio de biomarcadores en los defectos de la fosforilación oxidativa mitocondrial y en las deficiencias de coenzima CoQ10

Abstract

[spa] El objetivo general de este trabajo de tesis doctoral ha sido progresar en el desarrollo de biomarcadores para el estudio de pacientes con enfermedades mitocondriales. Los objetivos concretos han sido los siguientes:

1. Investigar nuevos biomarcadores para el diagnóstico y la investigación de enfermedades mitocondriales causadas por defectos OXPHOS: análisis de ADN mitocondrial libre circulante en muestras de líquido cefalorraquídeo de pacientes con enfermedades mitocondriales. 2. Analizar la concentración de coenzima Q10 en diferentes muestras biológicas con fines diagnósticos y de monitorización del tratamiento: determinación de coenzima Q10 en plasma, músculo, fibroblastos, orina, plaquetas y células mononucleares. 3. Desarrollar y validar un nuevo procedimiento para analizar las concentraciones de coenzima Q10 en plasma de pacientes con sospecha de enfermedad mitocondrial, para su posterior aplicación en otros especímenes biológicos para el diagnóstico de deficiencias de coenzima Q10.

[eng] Diagnosis and research of mitochondrial diseases (MD) remains challenging and there is a need for more sensitive and specific biomarkers that could contribute to easier categorization of these patients and prediction of clinical outcomes. Most routine biomarkers (e.g., lactate, pyruvate, alanine, urinary organic acids, or acylcarnitines) show poor sensitivity and specificity. Recently, it has been reported that cytokines GDF-15 and FGF-21 and plasma gelsolin can improve diagnostic specificity of MD, although altered levels have also been associated with a range of non-MDs. With the advances in next-generation sequencing (NGS) and the discovery of a variety of new disease-specific genes, the ability to diagnose MD has improved enormously. However, many patients with suspected MD remain without a genetic diagnosis, presenting a challenge for clinicians to counsel and manage them. Biomarkers for clinical outcome research are lacking as well. From the need for better biomarkers arises the main objective of this thesis: to progress the development of biomarkers for the study of patients with MD. The four publications in this work contribute to the advancement of the field of MD biomarkers and coenzyme Q10 (CoQ) deficiencies, by: 1) describing a new biomarker in cerebrospinal fluid for MD diagnosis and research; 2) demonstrating that the quantification of plasma CoQ concentrations are the best surrogate biomarker for monitoring oral CoQ treatment; 3) reporting the importance of the analysis of various biomarkers in the diagnosis of CoQ deficiencies; and 4) developing and validating a new method that allows the detection of CoQ deficiencies and the monitoring of oral CoQ treatment.