The role of mitochondrial metabolism in health and disease

Mitochondria are intracellular organelles that play a central role in metabolism. Aims of this thesis were to study the role of mitochondria in specific cases of rare inherited metabolic diseases, and to establish the nematode C. elegans as a model for resolving the relationship between metabolism, aging and mitochondrial disease. An example of how altered mitochondrial function affects organismal physiology is given by the profound effects of tetracycline antibiotics on various organisms through targeting of mitochondrial translation; their use in research as a tool to control gene expression may therefore confound the experimental outcome. In the case of the rare disease Perrault syndrome characterized by sensorineural deafness and gonadal dysgenesis, a novel mutation in the gene ERAL1 encoding a mitochondrial rRNA chaperone is identified through exome sequencing, functional mitochondrial assays and a C. elegans model. In Barth syndrome, a disease characterized mainly by cardioskeletal myopathy, neutropenia and abnormal mitochondria, and with unresolved pathophysiology, proteomic and metabolic profiling revealed altered metabolism in patient cells. Moreover, a sensitive platform to measure metabolites in C. elegans was established and utilized to detect age- and diet related changes in the nematode’s metabolome. Also, C. elegans knockdown of acl-3, the homologue of the human gene mutated in BTHS patients, mimicked the lipid disturbance seen in patients, establishing a valid model for the disease. Ultimately, advancements in the understanding of rare mitochondrial diseases, following a cross-species approach, can help to resolve the more complex processes that underlie aging and metabolic diseases.