Dataset Information

SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA

ABSTRACT: SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: angela cattaneo

LAB HEAD: Angela Bachi

PROVIDER: PXD047157 | Pride | 2024-05-24

REPOSITORIES: Pride

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			Action	DRS
	EZ_230307_SCE_1.raw	Raw
	EZ_230307_SCE_1_DBnew.mzid.gz	Mzid
	EZ_230307_SCE_1_DBnew.mzid_EZ_230307_SCE_1_DBnew.MGF	Mzid
	EZ_230317_EV.raw	Raw
	EZ_230317_EV_DBnew.mzid.gz	Mzid

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Publications

SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA.

Germani Serena S Van Ho Andrew Tri AT Cherubini Alessandro A Varone Ersilia E Chernorudskiy Alexander A Renna Giorgia Maria GM Fumagalli Stefano S Gobbi Marco M Lucchetti Jacopo J Bolis Marco M Guarrera Luca L Craparotta Ilaria I Rastelli Giorgia G Piccoli Giorgia G de Napoli Cosimo C Nogara Leonardo L Poggio Elena E Brini Marisa M Cattaneo Angela A Bachi Angela A Simmen Thomas T Calì Tito T Quijano-Roy Susana S Boncompagni Simona S Blaauw Bert B Ferreiro Ana A Zito Ester E

Cell reports. Medicine 20240222 3

Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ER-stress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of proteins. ERO1A depletion in SEPN1 knockout cells restores ER redox, re-equilibrates short-range MAMs, and rescues mitochondrial bioenergetics. ERO1A ...[more]

PMID: 38402623

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Project description:SEPN1 is a type II protein of the endoplasmic reticulum (ER) whose loss of function gives rise to a collection of debilitating autosomal recessive myopathies gathered under the umbrella term of SEPN1-related myopathy (RM). At the moment, SEPN1-RM lacks an effective pharmacological treatment; thus, the medical management of the disease is only supportive. The potentially fatal diaphragmatic weakness leading to respiratory insufficiency in patients still ambulant is the main reason for medical concerns. Thus, studies on SEPN1-RM pathogenesis are necessary to implement a targeted pharmacological therapy aimed at relieving the general muscle weakness and the more worrisome diaphragmatic dysfunction. Here, we show a physical and functional interaction between SEPN1 and the ER stress mediator ERO1 alpha (henceforth, ERO1). Both SEPN1 and ERO1 are involved in the redox regulation of proteins into the ER, although in an opposite way SEPN1 imposes a less oxidant ER poise while ERO1 a more oxidant one, conceivable with a reductase function of SEPN1 and an oxidase one of ERO1. Furthermore, both are mainly localized in a region of the ER in close contact with mitochondria termed mitochondria-associated membranes (MAMs) and their loss impacts oppositely on the short-range MAMs, thereby impinging ER-mitochondria Ca2+ dynamics, OXPHOS, and bioenergetics. We find that ERO1 depletion restores the impaired short-range MAMs due to SEPN1 loss together with mitochondrial ATP. ERO1 knockout in a mouse background of SEPN1 loss blunts ER stress and the consequent Unfolded Protein Response (UPR) while it rescues the diaphragmatic weakness by improving ER/mitochondria contacts, calcium dynamics, and OXPHOS. Importantly, treatments of SEPN1 knock out mice with the chemical chaperone tauroursodeoxycholic acid (TUDCA) mimic the results of ERO1 loss improving calcium dynamics, OXPHOS, ER/mitochondria contacts, thereby rescuing diaphragmatic weakness as well. In addition, TUDCA-treated SEPN1-RM patients-derived myoblasts show a dynamic dose-dependent increase in ATP levels under ER stress conditions suggesting improved mitochondrial function. Thus, our findings point to the ERO1 axis in the pathogenesis of SEPN1-RM thereby impinging on MAMs and mitochondria bioenergetics and recall for the efficacy of a pharmacology therapy with ad hoc ER stress/ERO1 inhibitors for SEPN1-RM.