Investigating the role of Mitochondrial Derived Peptides (MDPs) in metabolic diseases

Abstract

Introduction: Metabolic diseases contribute towards the leading causes of death and arise from dysfunctional metabolic processes in a single or more multiple organs due to impaired signaling and stress signals. Mitochondrial derived peptides (MDPs), a novel class of short proteins encoded by the mitochondrial genome (mtDNA), demonstrate protective effects during stress. One of these peptides named mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), augments and restores metabolic function in rodents during exercise and high-fat diet. Interestingly, genetic variants of MDPs exist that are likely to influence the structure and function, thereby contribute towards the risk for disease. By investigating naturally occurring polymorphisms present in the mtDNA, this thesis aimed to investigate how variant forms of the MDPs could have altered functions regulating metabolic processes associated with metabolic disease development. Methods and Results: A primary human skeletal muscle cell line was established from donors with differences in their endurance fitness phenotype to be used as a proxy model of human physiology. While the cells were unable to retain a metabolic phenotype of their donors, the cultured primary myotubes responded to fatty acid stress and MDP treatment. MOTS-c upregulated gene expression associated with a protective response during stress exposure, however, the MOTS-c variant K14Q did not exhibit similar effects in gene regulation. Sequencing of the mtDNA identified the polymorphism mt.6905A>G associated with postprandial hyperinsulinemia in young adults and was associated with increased risk for type 2 diabetes (T2D) in middle aged adults. The biggest finding of this thesis was the identification of three putative MDPs affected by this polymorphism and their native forms demonstrated an ability to rapidly reduce circulating insulin from an insulin bolus in mice. Additionally, in vitro, these putative MDPs increased cell viability in the basal and stress state. Conclusion: MDPs are novel functional small peptides and genetic variants of these are likely to alter their role in signaling events that are likely to increase disease risk. Three new MDPs from the natural polymorphism mt.6905A>G could regulate hyperinsulinemia, a risk factor for developing T2D. We have established a methodology to identify and test the physiological role of MDPs that could contribute towards metabolic disease onset.