Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria -ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induc-tion of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1a covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1a interaction requires the C-terminal active site of ERO1a and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1a complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organ-elles, while limiting oxidative stress. Therefore, the PERK-ERO1a complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria / Bassot, Arthur; Chen, Junsheng; Takahashi-Yamashiro, Kei; Yap, Megan C; Gibhardt, Christine Silvia; Le, Giang N T; Hario, Saaya; Nasu, Yusuke; Moore, Jack; Gutiérrez, Tomas; Mina, Lucas; Mast, Heather; Moses, Audric; Bhat, Rakesh; Ballanyi, Klaus; Lemieux, Hélène; Sitia, Roberto; Zito, Ester; Bogeski, Ivan; Campbell, Robert E; Simmen, Thomas. - In: CELL REPORTS. - ISSN 2211-1247. - 42:1(2023), p. 111899. [10.1016/j.celrep.2022.111899]
The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria
Sitia, Roberto;
2023-01-01
Abstract
Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria -ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induc-tion of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1a covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1a interaction requires the C-terminal active site of ERO1a and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1a complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organ-elles, while limiting oxidative stress. Therefore, the PERK-ERO1a complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.File | Dimensione | Formato | |
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