Redox activation of JNK2?2 mediates thyroid hormone-stimulated proliferation of neonatal murine cardiomyocytes.

ABSTRACT: Mitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H₂O₂). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H₂O₂ (mH₂O₂) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H₂O₂ that activates c-Jun N-terminal kinase-2?2 (JNK2?2). JNK2?2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation-this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.

SUBMITTER: Tan L 

PROVIDER: S-EPMC6881338 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature