Emerging role of LETM1/GRP78 axis in lung cancer

Quangdon Tran, Hyunji Lee, Jae Hun Jung, Seung Hee Chang, Robin Shrestha, Gyeyeong Kong, Jisoo Park, Seon Hwan Kim, Kyu Sang Park, Hyun Woo Rhee, Jeanho Yun, Myung Haing Cho, Kwang Pyo Kim, Jongsun Park

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


The selective autophagy of damaged mitochondria is called mitophagy. Mitochondrial dysfunction, mitophagy, and apoptosis have been suggested to be interrelated in various human lung carcinomas. Leucine zipper EF-hand-containing transmembrane protein-1 (LETM1) was cloned in an attempt to identify candidate genes for Wolf–Hirschhorn syndrome. LETM1 plays a role in mitochondrial morphology, ion homeostasis, and cell viability. LETM1 has also been shown to be overexpressed in different human cancer tissues, including lung cancer. In the current study, we have provided clear evidence that LETM1 acts as an anchoring protein for the mitochondria-associated ER membrane (MAM). Fragmented mitochondria have been found in lung cancer cells with LETM1 overexpression. In addition, a reduction of mitochondrial membrane potential and significant accumulation of microtubule-associated protein 1 A/1B-light chain 3 punctate, which localizes with Red-Mito, was found in LETM1-overexpressed cells, suggesting that mitophagy is upregulated in these cells. Interestingly, glucose-regulated protein 78 kDa (GRP78; an ER chaperon protein) and glucose-regulated protein 75 kDa (GRP75) were posited to interact with LETM1 in the immunoprecipitated LETM1 of H460 cells. This interaction was enhanced in cells treated with carbonyl cyanide m-chlorophenylhydrazone, a chemical mitophagy inducer. Treatment of cells with honokiol (a GRP78 inhibitor) blocked LETM1-mediated mitophagy, and CRISPR/Cas9-mediated GRP75 knockout inhibited LETM1-induced autophagy. Thus, GRP78 interacts with LETM1. Taken together, these observations support the notion that the complex formation of LETM1/GRP75/GRP78 might be an important step in MAM formation and mitophagy, thus regulating mitochondrial quality control in lung cancer.

Original languageEnglish
Article number543
JournalCell Death and Disease
Issue number6
Publication statusPublished - 2022 Jun

Bibliographical note

Funding Information:
This work was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (NRF-2021R1A2C1008492, NRF-2020R1F1A1049801, NRF-2021R1C1C200845611).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


Dive into the research topics of 'Emerging role of LETM1/GRP78 axis in lung cancer'. Together they form a unique fingerprint.

Cite this