Drp1 regulates transcription of ribosomal protein genes in embryonic hearts

Qiancong Zhao, Shun Yan, Jin Lu, Danitra J. Parker, Huiying Wu, Qianchuang Sun, David K. Crossman, Shanrun Liu, Qin Wang, Hiromi Sesaki, Kasturi Mitra, Kexiang Liu, Kai Jiao

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency-induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 in cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart fieldderived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes and embryonic lethality. By characterizing this model, we reveal an AMPK-SIRT7- GABPB axis that relays the reduced cellular energy level to decrease transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first genetic evidence in mouse that Drp1 is essential for RV development. Our research provides further mechanistic insight into how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

Original languageEnglish (US)
Article numberjcs258956
JournalJournal of Cell Science
Volume135
Issue number4
DOIs
StatePublished - 2022
Externally publishedYes

Keywords

  • Drp1
  • Heart development
  • RP gene transcription

ASJC Scopus subject areas

  • Cell Biology

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