Pitx2 maintains mitochondrial function during regeneration to prevent myocardial fat deposition

Development
Lele LiJames F Martin

Abstract

Loss of the paired-like homeodomain transcription factor 2 (Pitx2) in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, Pitx2 gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in Pitx2 conditional-knockout (Pitx2 CKO) mice. We found adipose-like tissue in Pitx2 CKO hearts 60 days after MI induced surgically at postnatal day 2 but not at day 8. Molecular and cellular analyses showed the onset of adipogenic signaling in mutant hearts after MI. Lineage tracing experiments showed a non-cardiomyocyte origin of the de novo adipose-like tissue. Interestingly, we found that Pitx2 promotes mitochondrial function through its gene regulatory network, and that the knockdown of a key mitochondrial Pitx2 target gene, Cox7c, also leads to the accumulation of myocardial fat tissue. Single-nuclei RNA-seq revealed that Pitx2-deficient hearts were oxidatively stressed. Our findings reveal a role for Pitx2 in maintaining proper cardiac cellular composition during heart regeneration via the maintenance of proper mitochondrial structure and funct...Continue Reading

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Citations

Nov 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Michelle M CollinsPia R Lundegaard
Aug 20, 2019·Reproductive Biology and Endocrinology : RB&E·Jingshun ZhangLianwen Zheng
Jun 16, 2019·Development·Matthew C HillJames F Martin
Oct 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Min ZhangJames F Martin
Jul 28, 2020·Circulation Research·Antoinette F van OuwerkerkVincent M Christoffels
Nov 23, 2020·Stem Cells Translational Medicine·Andia N Redpath, Nicola Smart
Apr 2, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Sandy M PayanFrancesca Rochais
Nov 12, 2018·Developmental Biology·Chih-Ning ChangChrissa Kioussi
Mar 7, 2021·International Journal of Molecular Sciences·Elvira ForteNadia A Rosenthal
Aug 14, 2019·Current Opinion in Cell Biology·Vaibhav DeshmukhJames F Martin
Apr 13, 2021·Cellular and Molecular Life Sciences : CMLS·Thai Q Tran, Chrissa Kioussi
Apr 7, 2021·Cell Regeneration·Lixia ZhengJing-Wei Xiong

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