Dataset Information

Mitochondria preconditioning delays aging and associated diseases in C. elegans impacting on key ferroptosis players

ABSTRACT: Excessive iron accumulation or deficiency have detrimental consequences across species, leading to a variety of pathologies in humans. In the nematode Caenorhabditis elegans severe iron as well as oxygen deprivation induce developmental arrest. Instead, hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage and sub-lethal levels of iron depletion extend lifespan in C. elegans. The positive health outcomes of applying hypoxia preconditioning are obvious but have low feasible application. Here, we thus assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protect against hypoxia-, age- and proteotoxicityinduced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are at least in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death specifically mediated by iron-induced lipid peroxidation. These is achieved by impacting on different key players of the ferroptosis machinery and likely via novel, gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel strategy to promote healthy aging.

INSTRUMENT(S):

ORGANISM(S): Caenorhabditis Elegans

TISSUE(S): Whole Body

SUBMITTER: Bernd Thiede

LAB HEAD: Hilde Loge Nilsen

PROVIDER: PXD040724 | Pride | 2023-04-17

REPOSITORIES: Pride

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			Action	DRS
	RB_151022_Hilde_1.mzid.gz	Mzid
	RB_151022_Hilde_1.mzid_RB_151022_Hilde_1.MGF	Mzid
	RB_151022_Hilde_1.raw	Raw
	RB_151022_Hilde_2.mzid.gz	Mzid
	RB_151022_Hilde_2.mzid_RB_151022_Hilde_2.MGF	Mzid

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Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players.

Schiavi Alfonso A Salveridou Eva E Brinkmann Vanessa V Shaik Anjumara A Menzel Ralph R Kalyanasundaram Sumana S Nygård Ståle S Nilsen Hilde H Ventura Natascia N

iScience 20230321 4

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C. elegans lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxyg ...[more]

PMID: 37020951

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Project description:Friedreich ataxia (FRDA) is a progressive neuromuscular degenerative disorder caused by GAA repeat expansions in the FXN gene, leading to frataxin deficiency and multisystem pathology. Cardiomyopathy is the leading cause of mortality in FRDA patients. To investigate the cellular and molecular mechanisms underlying FRDA-associated cardiac dysfunction, we employed induced pluripotent stem cell (iPSC) lines derived from three FRDA patients, each paired with an isogenic control line generated through CRISPR/Cas9-mediated excision of the pathogenic GAA repeat expansion. Correction of the mutation restored FXN expression to levels comparable to healthy donor iPSCs, and all lines differentiated efficiently into cardiomyocytes. Functional analysis revealed significant contractile abnormalities in FRDA cardiomyocytes and multicellular cardiac microtissues, including prolonged contraction and relaxation times and faster beating rates, consistent with clinical observations of cardiac contractile dysfunction. FRDA cardiomyocytes also exhibited pathological features such as increased cell size, irregular calcium transients, elevated mitochondrial reactive oxygen species levels, increased mitochondrial fission and increased cell death. These phenotypes were exacerbated by pathological levels of iron supplementation in culture media, highlighting the heightened sensitivity of frataxin-deficient cardiomyocytes to iron-induced metabolic stress. RNA sequencing revealed a distinct transcriptional profile associated with frataxin deficiency. MEG3 and PCDHGA10 were consistently dysregulated across all three FRDA-iPSC lines and may represent early molecular markers of FRDA cardiomyopathy. Together, these findings establish a robust human iPSC model of FRDA cardiomyopathy that captures early disease phenotypes and reveals novel molecular targets. This preclinical human model provides valuable insight into the pathogenesis of FRDA and provides a platform for developing early-stage therapeutic interventions.

Dataset Information

Mitochondria preconditioning delays aging and associated diseases in C. elegans impacting on key ferroptosis players

Dataset's files

Publications

Mitochondria hormesis delays aging and associated diseases in <i>Caenorhabditis elegans</i> impacting on key ferroptosis players.

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