METTL3 and ALKBH5 oppositely regulate m⁶A modification of <i>TFEB</i> mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes.

ABSTRACT: N⁶-methyladenosine (m⁶A) mRNA modifications play critical roles in various biological processes. However, no study addresses the role of m⁶A in macroautophagy/autophagy. Here, we show that m⁶A modifications are increased in H/R-treated cardiomyocytes and ischemia/reperfusion (I/R)-treated mice heart. We found that METTL3 (methyltransferase like 3) is the primary factor involved in aberrant m⁶A modification. Silencing METTL3 enhances autophagic flux and inhibits apoptosis in H/R-treated cardiomyocytes. However, overexpression of METTL3 or inhibition of the RNA demethylase ALKBH5 has an opposite effect, suggesting that METTL3 is a negative regulator of autophagy. Mechanistically, METTL3 methylates TFEB, a master regulator of lysos

SUBMITTER: Song H 

PROVIDER: S-EPMC6613905 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature