Evolutionary Diversity of the Mitochondrial Calcium Uniporter and Its Contribution to Cardiac and Vascular Homeostasis

Abstract

Altered cardiac energetics and calcium handling are characteristic features of cardiovascular disease. Mitochondria play a significant role in both cellular energy generation and calcium homeostasis and may be a key integration point of these two systems. Calcium uptake into mitochondria occurs via a recently identified mitochondrial calcium uniporter complex. In the first part of this thesis, I characterize the phylogenomic distribution of the uniporter’s membrane spanning pore (MCU) and regulatory subunits (MICU1 and MICU2). Homologs of both MCU and MICU1 tend to co-occur in all major branches of eukaryotic life but both have been lost along certain protozoan and fungal lineages. MICU2 represents a recent duplication of MICU1. Several bacterial genomes also contain putative MCU homologs that may represent prokaryotic calcium channels. The analyses indicate that the uniporter may have been an early feature of mitochondria. In the second part of this thesis, I perform transcriptome wide analysis of human and mouse cardiomyopathy datasets and identify MICU2, a regulatory component of the mitochondrial calcium uniporter, as one of six genes consistently upregulated in cardiac disease states. I test the hypothesis that increased MICU2 expression is cardio-protective by generating a global Micu2-/- mouse. These mice have diastolic dysfunction. Isolated Micu2-/- cardiomyocytes show altered sarcomere relaxation and cytosolic calcium reuptake kinetics and Micu2-/- ventricular tissue has transcriptional dysregulation of genes encoding sarcomere proteins and bZIP transcription factors. When exposed to two weeks of angiotensin 2, a pharmacologic hypertrophic stimuli, Micu2-/- mice exhibit both systolic and diastolic dysfunction. Together, these data point to a significant and previously unappreciated role for Micu2 in maintaining both cardiac and vascular homeostasis.