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

被引：1

作者：

Shiiba, Isshin ^{[1
]}

Ito, Naoki ^{[1
]}

Oshio, Hijiri ^{[1
]}

Ishikawa, Yuto ^{[1
]}

Nagao, Takahiro ^{[2
]}

Shimura, Hiroki ^{[3
]}

Oh, Kyu-Wan ^{[4
]}

Takasaki, Eiki ^{[1
]}

Yamaguchi, Fuya ^{[1
]}

Konagaya, Ryoan ^{[1
]}

Kadowaki, Hisae ^{[5
]}

Nishitoh, Hideki ^{[5
]}

Tanzawa, Takehito ^{[6
]}

Nagashima, Shun ^{[3
]}

Sugiura, Ayumu ^{[7
]}

Fujikawa, Yuuta ^{[8
]}

Umezawa, Keitaro ^{[9
]}

Tamura, Yasushi ^{[10
]}

Lee, Byung Il ^{[4
]}

Hirabayashi, Yusuke ^{[2
,11
]}

Okazaki, Yasushi ^{[7
]}

Sawa, Tomohiro ^{[12
]}

Inatome, Ryoko ^{[1
]}

Yanagi, Shigeru ^{[1
]}

机构：

[1] Gakushuin Univ, Fac Sci, Dept Life Sci, Lab Mol Biochem, Toshima, Tokyo 1718588, Japan

[2] Univ Tokyo, Sch Engn, Dept Chem & Biotechnol, Tokyo, 1138656, Japan

[3] Tokyo Univ Pharm & Life Sci, Sch Life Sci, Lab Regenerat Med, Tokyo 1920392, Japan

[4] Natl Canc Ctr, Res Inst, Goyang, Gyeonggi Do, South Korea

[5] Univ Miyazaki, Fac Med, Lab Biochem & Mol Biol, 5200 Kihara,Kiyotake, Miyazaki 8891692, Japan

[6] Osaka Univ, Inst Prot Res, Suita, Osaka 5650871, Japan

[7] Juntendo Univ, Intractable Dis Res Ctr, Grad Sch Med, Diagnost & Therapeut Intractable Dis, Bunkyo Ku, Tokyo, Japan

[8] Tokyo Univ Pharm & Life Sci, Sch Life Sci, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan

[9] Tokyo Metropolitan Inst Gerontol, Res Team Mech Aging, 35-2 Sakae Cho, Tokyo, Tokyo 1730015, Japan

[10] Yamagata Univ, Fac Sci, 1-4-12 Kojirakawa Machi, Yamagata 9908560, Japan

[11] Univ Tokyo, Sch Engn, Dept Bioengn, Tokyo 1138656, Japan

[12] Kumamoto Univ, Grad Sch Med Sci, Dept Microbiol, 1-1-1 Honjo,Chuo Ku, Kumamoto 8608556, Japan

来源：

NATURE COMMUNICATIONS | 2025年 / 16卷 / 01期

基金：

日本学术振兴会;

关键词：

ENDOPLASMIC-RETICULUM; MITOFUSIN; 2; SITES; ROS; PEROXIDATION; APOPTOSIS; DYNAMICS;

D O I：

10.1038/s41467-025-56666-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

共 1 条

[1] The PTPIP51 coiled-coil domain is important in VAPB binding, formation of ER-mitochondria contacts and IP3 receptor delivery of Ca2+ to mitochondria
Morotz, Gabor M.
Martin-Guerrero, Sandra M.
Markovinovic, Andrea
Paillusson, Sebastien
Russell, Matthew R. G.
Machado, Pedro M. Pereira
Fleck, Roland A.
Noble, Wendy
Miller, Christopher C. J.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2022, 10

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