Phd Dissertations

Upcoming and recent PhD dissertations from STEMM Research Program.

The Metabolic and Molecular Consequences of Mitochondrial Dysfunction in Mitochondrial Disease and Acquired Obesity

Time: 9 February 2019   12:00

Place: Biomedicum Helsinki, Lecture Hall 2, Haartmaninkatu 8, 00290 Helsinki

Opponent: Professor Maria Judit Molnar, Semmelweis University

Custos: Academy Professor Anu Wartiovaara



Mitochondrial diseases are the most common group of inherited metabolic disorders. The clinical symptoms of mitochondrial disease patients are highly variable, which makes both the diagnosis and the management exceptionally challenging. The molecular mechanisms of tissue-specificity and clinical variability in mitochondrial disorders are unknown. Currently, an effective pharmacological treatment and reliable single biomarkers that would sufficiently detect mitochondrial disorders are lacking.

Due to the often severe neurological symptoms of mitochondrial disease patients, primary care and research often focus on the characterization and management of the neuromuscular manifestations, while the numerous and comparatively secondary metabolic complications remain neglected. Obesity and diabetes, for example, are common among certain mitochondrial disease groups, and therefore the contribution of mitochondrial dysfunction in metabolically active tissues is needed in mitochondrial medicine. In the first part of this thesis, the aim was to study the role of mitochondria in adipose tissue in mitochondrial disease and in acquired obesity. The metabolic and molecular consequences of mitochondrial dysfunction were analysed in 26 mitochondrial disease patients with different types of causative mutations and compared to 30 age-matched controls. The study revealed that patients with recessive mutations in mitochondrial DNA polymerase (mitochondrial recessive ataxia syndrome, MIRAS) were associated with central obesity, large adipocytes, insulin resistance and metabolic syndrome, whereas patients with a primary mitochondrial DNA mutation (mitochondrial myopathy, encephalopathy, lactate acidosis and stroke-like episodes, MELAS/ maternally inherited diabetes and deafness, MIDD) had diabetes, lower volume of adipose tissue and less adipocytes. The molecular analysis of adipose tissue showed a reduction of mitochondrial biogenesis and oxidative capacity in MIRAS patients, and to a lesser extend also in MELAS/MIDD patients. The effect of acquired obesity on mitochondrial function in adipose tissue was further studied in 26 rare monozygotic twins discordant for body weight. In adipose tissue of the obese co-twins, mitochondrial oxidative metabolism was reduced and associated with whole-body insulin resistance and inflammation, present already before the clinical diagnosis of diabetes and other related complications of acquired obesity.

In the second part of this thesis, the aim was to study metabolic changes of mitochondrial and other muscle-manifesting disease patients, and to identify potential metabolic biomarkers for mitochondrial disease diagnostics. Targeted metabolomics analysis of blood and/or muscle samples from 25 primary mitochondrial disease patients, 16 unaffected carriers, six inclusion body myositis patients, 15 non-mitochondrial neuromuscular disease patients, and 30 age-matched controls revealed different metabolic profiles that pointed to disease-specific mechanisms of pathogenesis. Changes in metabolites of transsulfuration pathway were specific for primary mitochondrial disease and inclusion body myositis patients, whereas creatine depletion marked neuromuscular diseases, inclusion body myositis and infantile-onset spinocerebellar ataxia patients. Low blood and muscle arginine was specific for MELAS/MIDD patients. The metabolomics data showed that blood metabolic fingerprints are potential multi-biomarkers for diagnostics. By combining a minimum of four metabolites (sorbitol, alanine, cystathionine and myoinositol), we created a metabolic multi-biomarker that distinguished primary mitochondrial disorders with sensitivity of 76% and specificity of 95%. Moreover, our results suggested that detected metabolites from affected pathways could be considered and further studied as disease therapy targets.

In conclusion, this thesis highlights the role of mitochondria in obesity. It reveals that different mitochondrial genetic defects provoke different consequences to systemic metabolism, leading to a disease-specific metabolic phenotype - obesity or leanness. The thesis further highlights the insufficiency of mitochondrial oxidative capacity in the adipose tissue of the obese subjects and its association with metabolic complications in acquired obesity. It also shows that targeted metabolomics analysis is a valuable tool in personalized medicine for suggesting metabolic targets for treatment and diet.