From the beginning to the end: the story of a mitochondrial disease

Resumen del trabajo presentado en el Workshop Mitochondrial homeostasis and human disease, celebrado en Girona (España) del 21 al 24 de septiembre de 2021.Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. We have reported that haploinsufficiency of ADCK2 in humans is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the aetiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data. We showed that Adck2+/− mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy specific of skeletal muscle. Significant decrease in Coenzyme Q (CoQ) levels was observed. These results indicate that ADCK2 is involved in fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. In order to evaluate if transgenic mouse phenotype could be altered since the early development, we decide to study the embryonic development of our mice to identify potential alterations. We also analysed the effect of prenatal CoQ10 administration during embryonic development and aging. In parallel, we have developed an ex-vivo model of our mice using adult muscle stem cells to study skeletal muscle cells specification and differentiation process during aging, and an in-vivo assessing of adult muscle stem cells after inducing skeletal muscle regeneration. We also evaluate these processes in skeletal muscle cells from mice supplemented with CoQ10. We have also assessed the progression of the phenotype of the mice to understand the progressive impairment that skeletal muscle shows during aging. The description of embryonic development and the study of aged mice could help to evaluate if the damages start during embryonic development and its progression during aging while CoQ10 prenatal administration could help to examine a potential approach for mitochondrial diseases.Peer reviewe