Mitochondrial Bioenergetics and Supercomplexes in Heart Failure: Mechanisms and Therapeutic Approaches

Abstract

Heart failure affects over 50 million people worldwide with increasing rates attributable to an aging population, improved survival following cardiovascular events, and high prevalence of risk factors. Many pharmacological approaches exist for disease management requiring complex individualized care that is further complicated by comorbidities. Given this landscape, characterizing the underlying mechanisms that contribute to reduced cardiac function at each disease stage is critical to design new and complementary therapeutic approaches. Changes in mitochondrial metabolism are evident throughout the progression of heart failure and largely include irregular substrate metabolism, alterations in mitochondrial energetics, reactive oxygen species signaling, and an imbalance in mitochondrial dynamics. This thesis explores novel bioenergetic aspects of mitochondrial supercomplexes and characterizes cardioprotective interventions and mitochondrial mechanisms involved in heart failure. First, we investigated the formation of mitochondrial supercomplexes, higher-order structures of the electron transport chain, which are thought to improve oxidative phosphorylation efficiency and limit mitochondrial reactive oxygen species emission. We hypothesized that interaction sites between complex I and complex III are critical for supercomplex formation. By designing a cell culture model with point mutations disrupting these interactions, we identified the role of NDUFB4, a non-catalytic subunit in supercomplex formation and characterized the bioenergetic, redox and metabolic changes induced by altered supercomplex formation. Furthering this work, we explored supercomplex formation in the heart where decreased assembly has been observed in cardiovascular diseases. Using a complexome profiling approach, which combines Native gel electrophoresis and mass spectrometry, we characterized the proteome composition of mitochondrial supercomplexes in a murine model of heart failure. We identified changes in the relative abundance of electron transport chain proteins, redox-related proteins, ribosome proteins and metabolic proteins within supercomplex bands. Next, we explored the involvement of a mitochondrial inner membrane protein, optic atrophy protein-1 (OPA1), in human heart pathology. Bioinformatic analyses of histological and transcript data indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were correlated with fatty acid, branch chain amino acid and contractile gene signatures. Complementary in vivo work employing a 1.5-fold whole body OPA1 overexpression mouse model identified a protective effect of OPA1 in improving cardiac function in response to pressure-overload induced heart failure. Finally, we sought to explore cardioprotection and metabolic changes induced by glucagon-like peptide-1 receptor (GLP-1R) agonists. Using a high-fat high-cholesterol diet model combined with a myocardial infarction (MI) model, we evaluated the impact of the GLP-1R agonist, semaglutide, in mediating changes in cardiac function, myocardial metabolic remodeling, and reactive oxygen species emission. We identified time-dependent effects on cardioprotection with post-MI treatment improving exercise capacity but not cardiac function, whereas pre-MI treatment attenuated decreases in cardiac function. No changes in ex vivo cardiac mitochondrial bioenergetic capacity or reactive oxygen species emission were induced with either treatment paradigm. Overall, this thesis work has advanced our understanding of mitochondrial supercomplex formation and how the mitochondrial complexome changes in heart failure. Moreover, we identify both genetic (OPA1) and therapeutic (GLP-1R agonist) interventions that confer cardioprotection in murine heart failure models and characterize the involvement of mitochondrial pathways in heart failure.