Dataset Information

Optic Atrophy 1 (OPA1) overexpression promotes dyslipidemia and atherosclerosis coupled to altered aortic VSMC function in LDL-R deficient mice.

ABSTRACT: Aims: Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, sterol and bile acids (BAs) synthesis. Mitochondria are plastic organelles and continuously undergo biogenesis, fusion, fission and mitophagy. On these premises, we tested how the overexpression of OPA1, an inner mitochondrial membrane fusion protein, impacts lipids, lipoprotein metabolism and atherosclerosis development in LDL-R deficient mice (LDLR KO). Methods: OPA1TG/LDLR KO and OPA1ΔHep /LDLR KO were generated and fed with a Western-type diet (WTD) for 12 weeks. Atherosclerosis development was compared to that of LDLR KO mice. In humans, OPA1 expression was investigated in samples from 78 asymptomatic and symptomatic human subjects within the Carotid Plaque Imaging Project (CPIP). Results: OPA1TG/LDLR KO mice showed a significant increase in plasma cholesterol levels mainly in VLDL and LDL fractions. OPA1TG/LDLR KO display a reduction of unconjugated bile acids and higher percentage of conjugated bile acids leading to an increased lipid adsorption. This phenotype was associated with increased atherosclerosis in the aortic root. OPA1 overexpression affects also vascular smooth muscle cell cellular metabolism, leading to an increase in the synthetic vs the proliferative phenotype. Vice versa, hepatocyte deletion of OPA1 improved systemic lipoprotein metabolism and protected from atherosclerosis. The analysis of human atherosclerotic samples indicated that a higher OPA1 expression in the plaque is associated with a reduced degradation of extracellular matrix as well as the expression of markers of cell migration and differentiation. Conclusion: Mitochondrial fusion mediated by OPA1 plays a key role in atherosclerosis by affecting lipoprotein metabolism as well as vascular smooth muscle cell biology.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Giovanni Battista Vingiani

LAB HEAD: Giuseppe Danillo Norata

PROVIDER: PXD060456 | Pride | 2025-10-27

REPOSITORIES: Pride

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Increased mitochondrial fusion via systemic OPA1 overexpression promotes dyslipidemia and atherosclerosis in LDLR deficient mice.

Da Dalt Lorenzo L Fantini Francesca F Giancane Giulia G Moregola Annalisa A Roda Silvia S Svecla Monika M Pedretti Silvia S Vingiani Giovanni Battista GB Sun Jiangming J Edsfeldt Andreas A Goncalves Isabel I Uboldi Patrizia P Donetti Elena E Baragetti Andrea A Mitro Nico N Scorrano Luca L Norata Giuseppe Danilo GD

Molecular metabolism 20250922

<h4>Objective</h4>Mitochondria are involved in cellular metabolism, energy production, calcium homeostasis, and the synthesis of sterols and bile acids (BAs). Emerging evidence suggests that mitochondrial dynamics including biogenesis, fusion, fission, and mitophagy critically influence cardiometabolic diseases, yet their role in atherogenesis remain poorly understood. Mitochondrial fusion ensures metabolic flexibility and stress adaptation, processes highly relevant to lipid handling and vascul ...[more]

PMID: 40992730

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Project description:Adipose tissue inflammation and atherosclerosis are the main mechanisms behind type 2 diabetes and cardiovascular disease respectively, the major risks associated with the metabolic syndrome. Studies considering more than single factors behind the complexity of the metabolic syndrome are valuable to achieve a better and wider understanding of the metabolic syndrome. In this study common dysregulated pathways between adipose tissue inflammation and atherosclerosis were identified using two different bioinformatic tools to perform pathway analysis. First, we run a gene set enrichment analysis utilizing with data from two microarray experiments done with gonadal white adipose tissue and atherosclerotic aorta. Once the common dysregulated pathways between both tissues were identify, the inflammatory response and the oxidative phosphorylation pathways from the Hallmark geneset were selected to conduct a deeper checkup at the single gene level of these pathways. Second, we carried out a pathway analysis validation with the Pantherâ¢ software combining the microarray data with a published type 2 diabetes mellitus metanalysis and cardiovascular disease metanalysis which included human data. In conclusion, this study provides worthwhile data pointing out and describing several dysregulated and common pathways in adipose tissue inflammation and atherosclerotic aorta with a potential implication in the pathogenesis of type 2 diabetes and atherosclerosis. LDLR-/- on a C57BL/6J background, purchased from Charles River Laboratories (Sulzfeld, Germany) were used. At 9 weeks of age the LDLR-/- were placed for up to 20 weeks on sucrose-enriched high-fat diet (HFSC) (with 17.5 kcal% from sucrose; (D09071704, Research Diets Inc.). Their respective controls were kept on normal chow diet (NC) for up to 20 weeks. After sacrificing the gonadal white adipose tissue (GWAT) from LDLR-/- animals on NC (Samples 22-27) or HFSC (Samples 28-33) was collected as well as the whole aortae from LDLR-/- animals on NC (Samples 13-15) or HFSC (Samples16-18). The collected tissues were immediately snap frozen in liquid nitrogen. RNA was isolated for gene expression microarray analyses at the exon level (GeneChip Mouse Exon 2.0 ST Array, Affymetrix, Santa Clara, CA, USA). To isolate RNA, the frozen tissue samples were homogenized in TRIzolÂ® reagent (Invitrogen/Life Technologies, Carlsbad, CA, USA) and processed based on manufacturerâs instructions. Total RNA (1Î¼g) was then used for GeneChip analysis, individual samples were used in GWAT preparation and three samples were pooled and used for aorta preparations. Terminal-labeled cDNA, hybridization to genome-wide Mouse Gene 2.0 ST Gene Chips and scanning of the arrays were carried out according to the manufactureâs indications (Affymetrix).Output primary row data was analyzed with Expression Console software (Affymetrix).

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	Aorta1TG.raw	Raw
	Aorta1WT.raw	Raw
	Aorta2TG.raw	Raw
	Aorta2WT.raw	Raw
	Aorta3TG.raw	Raw