Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Jones, Steven P.

Committee Co-Chair (if applicable)

Clark, Barbara

Committee Member

Clark, Barbara

Committee Member

Hill, Bradford

Committee Member

Clem, Brian

Author's Keywords

PANK1; heart failure; pressure overload; ventricular remodeling; Coenzyme A; CoA


Recent studies have associated elevated protein acetylation levels with heart failure in humans. Although mechanisms promoting elevated acetylation levels are not fully known, excess acetyl-CoA may drive enzyme-independent acetylation of cardiac proteins. Accumulation of acetyl-CoA depends on the availability of sufficient CoA, whose production is regulated by pantothenate kinases in the CoA biosynthetic pathway. We show that cardiac proteins are hyperacetylated during heart failure in humans and tested in mice whether limiting CoA abundance would improve ventricular remodeling during pressure overload-induced hypertrophy. We limited cardiac CoA levels by deleting the rate-limiting enzyme in CoA biosynthesis, Pank1 (one of three PANK-encoding genes in mice). We reasoned that this strategy would at least partially limit the driving force (excess acetyl-CoA) for acetylation in the failing heart. We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1-/-) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared to Pank1 sufficient littermates (cmPank1+/+) but exerted no obvious deleterious impact on the mice. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, despite limiting acetyl-CoA and acetylation levels in cmPank1-/- mice, there was more ventricular dilation in cmPank1-/- during pressure overload. To explore potential mechanisms contributing to this unanticipated result, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Lastly, coincident with increased acetylation observed during heart failure, mitochondrial respirasomes (supercomplexes) composition was changed during heart failure and may contribute to reduced mitochondria efficiency; however, it is not known whether acetylation directly affects mitochondrial respirasomes. We showed that reducing mitochondria acetylation alone does not impact mitochondria respirasomes, mitochondria function, or mitochondria dynamics. Furthermore, we did not observe any significant impact in mitochondrial supercomplexes when mitochondria hyperacetylation was induced. Briefly, our study underscores the role of elevated CoA levels (via Pank1) in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart. We also showed that changing mitochondrial acetylation alone does not impact mitochondria supercomplexes.