ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress

Isshin Shiiba (), Naoki Ito, Hijiri Oshio, Yuto Ishikawa, Takahiro Nagao, Hiroki Shimura, Kyu-Wan Oh, Eiki Takasaki, Fuya Yamaguchi, Ryoan Konagaya, Hisae Kadowaki, Hideki Nishitoh, Takehito Tanzawa, Shun Nagashima, Ayumu Sugiura, Yuuta Fujikawa, Keitaro Umezawa, Yasushi Tamura, Byung Lee, Yusuke Hirabayashi, Yasushi Okazaki, Tomohiro Sawa, Ryoko Inatome and Shigeru Yanagi ()
Additional contact information
Isshin Shiiba: Toshima
Naoki Ito: Toshima
Hijiri Oshio: Toshima
Yuto Ishikawa: Toshima
Takahiro Nagao: The University of Tokyo
Hiroki Shimura: Hachioji
Kyu-Wan Oh: Goyang‐si
Eiki Takasaki: Toshima
Fuya Yamaguchi: Toshima
Ryoan Konagaya: Toshima
Hisae Kadowaki: Kiyotake
Hideki Nishitoh: Kiyotake
Takehito Tanzawa: Suita
Shun Nagashima: Hachioji
Ayumu Sugiura: Bunkyo-ku
Yuuta Fujikawa: Hachioji
Keitaro Umezawa: Itabashi-ku
Yasushi Tamura: Yamagata
Byung Lee: Goyang‐si
Yusuke Hirabayashi: The University of Tokyo
Yasushi Okazaki: Bunkyo-ku
Tomohiro Sawa: Chuo-ku
Ryoko Inatome: Toshima
Shigeru Yanagi: Toshima

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.

Date: 2025
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DOI: 10.1038/s41467-025-56666-4

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