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Mitochondrial fuels ATP in the nucleus to prevent cell cycle arrest during mechanical confinement

ABSTRACT: Abstract The physical microenvironment regulates cell behaviour during tissue development and disease. Whether mechanical stress and physical space constraints reshape the subcellular localization of organelles and proteins resulting in functional adaptations is, however, unknown. Here, we performed proteomic analysis to understand how proteins reorganise between the nucleus and the cytoplasm when cancer cells are acutely confined. We discovered that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that upon confinement mitochondria, in an actin-dependent manner, are trapped within an ER-based net that indents the nucleus. At the functional level, the close proximity of mitochondria and the nucleus results in a nuclear ATP surge, which is reverted by inhibiting ATP mitochondrial export or actin polymerisation. Pharmacological prevention of this confinement-induced nuclear ATP surge impedes cell proliferation through cell cycle defects. Taken together, our data indicates that the physical association between the nucleus and mitochondria is a functional requirement for cell cycle completion after acute mechanical stress.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Hela Cell

DISEASE(S): Cervix Carcinoma

SUBMITTER: Savvas Kourtis

LAB HEAD: Sara Sdelci

PROVIDER: PXD043524 | Pride | 2025-06-12

REPOSITORIES: Pride

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			Action	DRS
	EC_118-M990-A01-P11906-1.raw	Raw
	EC_118-M990-A02-P11907-1.raw	Raw
	EC_118-M990-A03-P11908-1.raw	Raw
	EC_118-M990-A04-P11909-1.raw	Raw
	EC_118-M990-A05-P11910-1.raw	Raw

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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.

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Mitochondrial fuels ATP in the nucleus to prevent cell cycle arrest during mechanical confinement

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