Unravelling the molecular mechanisms underlying mitochondrial dysfunction in metabolic diseases

Mitochondria are the powerhouses of the cell and their function is often disturbed in disease, especially in metabolic diseases, like myopathies and non-alcoholic steatohepatitis (NASH). The cause-consequence relationship herein is however poorly understood. In this thesis, molecular mechanisms are studied that underlie mitochondrial dysfunction in unexplained myopathies as well as in NASH. Moreover, experimental therapies making use of carbon monoxide-releasing molecules (CORMs) are explored to improve mitochondrial health. The effects of mitochondrial DNA (mtDNA) methylation on mitochondrial gene expression points to a layer of epigenetic regulation that may play a role in disease initiation and/or progression. In this thesis, we study the effects of mtDNA methylation in NASH and myopathy. Increase in mtDNA methylation is associated with a decrease in energy production and this sets out a possible cause for mitochondrial dysfunction. Additional work presented in this thesis shows that mitochondrial function can be improved and enhanced using compounds such as carbon monoxide (CO). As CO can potentially alleviate mitochondrial respiratory impairment and is known to promote liver regeneration, it can be used to treat chronic diseases like NASH.In conclusion, this thesis supports a role for mtDNA methylation in promoting mitochondrial dysfunction, impaired lipid metabolism and loss of ATP-generating capacity and highlights potential therapeutic interventions based on CO that may potentially attenuate the development of metabolic diseases