Abstract 16665: Tead1 - a Novel Cell-Autonomous Regulator of Mitochondrial Function in Cardiomyocytes

Abstract

Introduction: Mitochondrial (mito) dysfunction occurs in most forms of heart failure (HF). We previously demonstrated that TEAD1, the transcriptional effector of Hippo pathway, plays a critical non-redundant role in adult CM homeostasis and its loss-of-function (LOF) leads to rapid-onset HF and dilated cardiomyopathy (DCM). Objective of this study was to determine requirement of TEAD1 in regulation of mito function in CMs. Hypothesis: TEAD1 is required for normal CM mito function and a loss of this regulation contributes to the rapid-onset lethal DCM with Tead1 deletion. Methods and Results: Conditional Tead1 deletion in adult CMs ( Tead1 -icKO) was achieved after 3 wks of tamoxifen (TM) diet in 6 wks old mutant mice (floxed Tead1, Tead1 F/F mice crossed with Myh6-CreER mice ) . Within 3 wks of Tead1 deletion, Tead1 -icKO mice developed acute lethal DCM with LV dilation and severe systolic dysfunction. Gene-set enrichment analysis from the Tead1 -icKO myocardial transcriptome, followed by qPCR validation, revealed mito-related genes as the top regulated gene sets. ChIP-seq, using TEAD1 antibody, in adult mouse hearts revealed that TEAD1 occupies the promoter/enhancers of multiple genes regulating mito biogenesis and function. To investigate if TEAD1 regulates OXPHOS, mito oxygen consumption rates (OCR) from mitochondria isolated from control and Tead1 -icKO mouse hearts were analyzed by Oroboros respirometry. Tead1 -icKO heart mitochondria had significantly decreased OCR with both palmitoylcarnitine and pyruvate/malate substrates. Primary neonatal CMs with ex vivo TEAD1 LOF (adenoviral-Cre transduction of Tead1 F/F neonatal CMs) showed diminished maximal OCR (Seahorse XF24 analyzer), demonstrating that TEAD1 regulation of OXPHOS in CMs is cell autonomous. (Refer to Fig) Conclusions: Taken together, our data demonstrate that TEAD1 is a direct transcriptional regulator of a large network of mitochondrial function and biogenesis related genes, is a novel cell-autonomous regulator of CM mitochondrial function and is critical for maintenance of adult CM homeostasis.