The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria

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.

Automated summary

Endoplasmic reticulum (ER) homeostasis relies on molecular regulators, such as calnexin and NOX4, to maintain mitochondrial metabolism and ER-mitochondria contacts. During ER stress induction, the PERK-ERO1a complex interacts and promotes oxidation of MERC proteins, controlling mitochondrial dynamics and improving ER-mitochondria Ca2+ flux for bioenergetics maintenance. This complex plays a crucial role in quick metabolic adaptation to ER stress.