Uncovering the Localization and Function of a Novel Read-Through Transcript ' TOMM40-APOE'

Shichen Chang; Satoru Torii; Jun Inamo; Kinya Ishikawa; Yuta Kochi; Shigeomi Shimizu

doi:10.3390/cells13010069

Uncovering the Localization and Function of a Novel Read-Through Transcript ' TOMM40-APOE'

Cells. 2023 Dec 28;13(1):69. doi: 10.3390/cells13010069.

Authors

Shichen Chang^{1

2}, Satoru Torii¹, Jun Inamo³, Kinya Ishikawa², Yuta Kochi³, Shigeomi Shimizu¹

Affiliations

¹ Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
² Department of Personalized Genomic Medicine for Health, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
³ Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Abstract

Recent advancements in genome analysis technology have revealed the presence of read-through transcripts in which transcription continues by skipping the polyA signal. We here identified and characterized a new read-through transcript, TOMM40-APOE. With cDNA amplification from THP-1 cells, the TOMM40-APOE3 product was successfully generated. We also generated TOMM40-APOE4, another isoform, by introducing point mutations. Notably, while APOE3 and APOE4 exhibited extracellular secretion, both TOMM40-APOE3 and TOMM40-APOE4 were localized exclusively to the mitochondria. But functionally, they did not affect mitochondrial membrane potential. Cell death induction studies illustrated increased cell death with TOMM40-APOE3 and TOMM40-APOE4, and we did not find any difference in cellular function between the two isoforms. These findings indicated that the new mitochondrial protein TOMM40-APOE has cell toxic ability.

Keywords: APOE; TOMM40; cell death; gene fusion; mitochondria; read-through transcript.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apolipoprotein E3
Apolipoprotein E4*
Apolipoproteins E*
Cell Death
DNA, Complementary

Substances

Apolipoprotein E4
Apolipoprotein E3
Apolipoproteins E
DNA, Complementary

Grants and funding

This study was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (S) (23H05480), (A) (20H00467), Grant-in-Aid for JSPS Fellows (21J00596), and MEXT KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas (17H06414, 22H04639, 23H04773). This study was also supported by AMED-CREST (JP23gm1410012) and the Project for Psychiatric and Neurological Disorders (JP21wm0525028) from the Japan Agency for Medical Research and Development, AMED. This study was also supported by the Joint Usage/Research Program of the Medical Research Institute and Medical Research Center Initiative for High Depth Omics, Tokyo Medical and Dental University.