The RNA Demethylase ALKBH5 Maintains Endoplasmic Reticulum Homeostasis by Regulating UPR, Autophagy, and Mitochondrial Function

Panneerdoss Subbarayalu, Pooja Yadav, Santosh Timilsina, Daisy Medina, Kunal Baxi, Robert Hromas, Ratna K. Vadlamudi, Yidong Chen, Patrick Sung, Manjeet K. Rao

Research output: Contribution to journalArticlepeer-review

Abstract

Eukaryotic cells maintain cellular fitness by employing well-coordinated and evolutionarily conserved processes that negotiate stress induced by internal or external environments. These processes include the unfolded protein response, autophagy, endoplasmic reticulum-associated degradation (ERAD) of unfolded proteins and altered mitochondrial functions that together constitute the ER stress response. Here, we show that the RNA demethylase ALKBH5 regulates the crosstalk among these processes to maintain normal ER function. We demonstrate that ALKBH5 regulates ER homeostasis by controlling the expression of ER lipid raft associated 1 (ERLIN1), which binds to the activated inositol 1, 4, 5,-triphosphate receptor and facilitates its degradation via ERAD to maintain the calcium flux between the ER and mitochondria. Using functional studies and electron microscopy, we show that ALKBH5-ERLIN-IP3R-dependent calcium signaling modulates the activity of AMP kinase, and consequently, mitochondrial biogenesis. Thus, these findings reveal that ALKBH5 serves an important role in maintaining ER homeostasis and cellular fitness.

Original languageEnglish (US)
Article number1283
JournalCells
Volume12
Issue number9
DOIs
StatePublished - May 2023

Keywords

  • ALKBH5
  • ER homeostasis
  • ERLIN1
  • autophagy
  • m6A
  • mitochondria
  • unfolded protein response

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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