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Principal Investigator: Nuo Sun
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $522,831
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Mitochondrial dysfunction and altered mitochondrial metabolism have been implicated in the development
of heart failure (HF). Mitophagy is a specialized autophagic pathway that mediates the lysosome-dependent
clearance of damaged mitochondria, and is essential for mitochondrial quality control. However, our current
knowledge regarding mitophagy in the heart and how it relates to myocardial metabolism is limited. Under normal
conditions, the heart relies predominantly on fatty acid β-oxidation (FAO) to fuel ATP production. In contrast, a
failing or hypertrophied heart usually shows impaired FAO and increased reliance on glucose utilization. Despite
significant advancements in understanding the regulatory programs that attenuate FAO, it is unclear how shifts
in myocardial substrate utilization contribute to the regulation of mitophagy. Therefore, this research proposal
focuses on the functional significance of cardiac mitophagy in response to altered myocardial substrate utilization
that occurs, for instance, in the setting of impaired FAO. The goal of this project is to delineate the novel
mechanistic link between mitophagy and myocardial substrate utilization in the heart, as well as to determine
whether mitophagy represents a novel mechanism and therapeutic target for the treatment of heart disease.
These studies will be facilitated by our recently described mt-Keima mouse model to monitor in vivo cardiac
mitophagy, as well as a set of innovative reagents to genetically and pharmacologically modulate mitophagic
flux. To directly assess the role of FAO in the heart, we have generated mice with cardiomyocyte-specific deletion
of CPT2 (CPT2-cKO), encoding a single gene required for FAO. We have demonstrated a decline in mitophagy
precedes the development of impaired cardiac function in FAO-deficient hearts. Our genetic analyses suggest
cardiac CPT2 deletion impairs the PTEN-induced putative kinase 1 (PINK1) signaling pathway, which positively
regulates mitophagy through mitochondrial ubiquitination. Augmentation of mitophagy by modulating USP30,
which mediates the reverse reaction, deubiquitination on mitochondria, mitigates the functional decline in FAO
deficient hearts. Therefore, in Aim 1 of the proposed studies, our goal is to define the magnitude and Kinetics of
cardiac mitophagy in response to impaired FAO, as well as to dissect the underlying molecular mechanisms
connecting mitophagy to myocardial substrate utilization. In Aim 2 of the proposed studies, we will genetically
and pharmacologically manipulate USP30 enzymatic function in the heart using mouse models that lack USP30
or are treated with a novel USP30 inhibitor. We will determine whether the detrimental cardiac phenotype,
induced by cardiac CPT2 deletion or pressure overload, could be reversed, at least partially, by restoring
mitophagy in cardiomyocytes via the inhibition of USP30. Completion of the proposed studies will produce critical
insights into the role of mitophagy in normal cardiovascular physiology and in pathological conditions, and will
fundamentally advance our understanding of the interaction between mitochondrial metabolism and
mitochondrial quality control in the heart.
Terms: <21+ years old><APF-1><ATP-Dependent Proteolysis Factor 1><Adult><Adult Human><Affect><Attenuated><Autoregulation><Bioenergetics><Body Tissues><CPT 1><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Carnitine Acyltransferase I><Carnitine O-Palmitoyltransferase><Carnitine Palmitoyltransferase><Carnitine Palmitoyltransferase I><D-Glucose><Deubiquitinating Enzyme><Deubiquitination><Development><Dextrose><E3 Ligase><E3 Ubiquitin Ligase><Energy Expenditure><Energy Metabolism><Esteroproteases><Exhibits><Fatty Acids><Genes><Genetic><Genetic analyses><Glucose><Goals><HMG-20><Heart><Heart Diseases><Heart Hypertrophy><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><High Mobility Protein 20><Homeostasis><Human><Impairment><In Vitro><Inner mitochondrial membrane><Intermediary Metabolism><Intervention><Intervention Strategies><Kinases><Kinetics><Knock-out><Knockout><Knowledge><Link><Lysosomes><MMAC1><MMAC1 protein><Mediating><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Mitochondrial Membrane Protein><Modeling><Modern Man><Molecular><Murine><Mus><Mutated in Multiple Advanced Cancers 1><Myocardial><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Nuclear><Outer Mitochondrial Membrane><PARK6><PARK6 gene><PARK6 protein><PHTS gene><PHTS protein><PINK1><PINK1 gene><PINK1 gene product><PINK1 protein><PTEN><PTEN gene><PTEN induced kinase 1><PTEN induced putative kinase 1><PTEN protein><PTEN-induced putative kinase><PTEN1><Palmitoylcarnitine Transferase><Palmitylcarnitine Acyltransferase><Parkin><Parkin gene><Parkinson disease 6 gene><Pathologic><Pathway interactions><Peptidases><Peptide Hydrolases><Phenotype><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphatase and tensin homolog induced kinase 1><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiological Homeostasis><Play><Production><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Quality Control><Reaction><Reagent><Receptor Protein><Regulation><Research><Research Proposals><Role><Signal Pathway><Stress><Testing><Therapeutic><Tissues><Transphosphorylases><Ubiquitilation><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><adulthood><attenuate><attenuates><cardiac failure><cardiac function><cardiac hypertrophy><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cardiovascular function><carnitine palmitoyltransferase 1><carnitine palmitoyltransferase 2 deficiency><carnitine palmitoyltransferase II deficiency><circulatory system><de-ubiquitinase><de-ubiquitinating enzyme><decline in function><decline in functional status><developmental><function of the heart><functional decline><functional status decline><gain of function><genetic analysis><heart disorder><heart function><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><improved><in vivo><in vivo monitoring><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inhibitor><innovate><innovation><innovative><insight><interventional strategy><long chain fatty acid><mitochondrial><mitochondrial dysfunction><mitochondrial metabolism><mouse model><murine model><mutated in multiple advanced cancers 1 protein><myocardium disease><myocardium disorder><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidation><parkin protein><pathway><pharmacologic><phosphatase and tensin homologue on chromosome ten><premature><prematurity><presenilin><preservation><pressure><programs><protein kinase BRPK><protein kinase BRPK gene><receptor><response><rhomboid><serine/threonine-protein kinase PINK1><social role><spatiotemporal><therapeutic target><treatment strategy><ubiquination><ubiquitin conjugation><ubiquitin isopeptidase><ubiquitin-protein ligase><ubiquitin-specific isopeptidase>