RT Journal Article
T1 Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm
A1 Oller, Jorge
A1 Gabandé-Rodriguez, Enrique
A1 Ruiz-Rodríguez, Maria Jesús
A1 Desdín-Micó, Gabriela
A1 Aranda Gómez, Juan Francisco
A1 Ballesteros-Rodríguez, Constanza
A1 Blanco, Eva Maria
A1 Roldán-Montero, Raquel
A1 Acuña, Pedro
A1 Forteza-Gil, Alberto
A1 Martín-López, Carlos
A1 Nistal, Francisco
A1 Lino Cardenas, Christian
A1 Evan, Lindsay
A1 Martín-Vertura, Jose Luis
A1 Briones, Ana
A1 Redondo, Juan Miguel
A1 Mittelbrunn, María
AB Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.Methods: Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model (Fbn1c1039g/+) and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; Myh11-CreERT2Tfamflox/flox mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration.Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young Fbn1c1039g/+ mice. In vitro experiments in Fbn1-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in Fbn1c1039g/+ mice.Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
SN 0009-7322
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/94925
UL https://hdl.handle.net/20.500.14352/94925
LA eng
NO Oller, Jorge, et al. «Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm». Circulation, vol. 143, n.o 21, mayo de 2021, pp. 2091-109. https://doi.org/10.1161/CIRCULATIONAHA.120.051171.
NO This study was supported by the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI16/188, PI19/855), the European Regional Development Fund, and the European Commission through H2020-EU.1.1, European Research Council grant ERC-2016-StG 715322-EndoMitTalk, and Gobierno de España SAF2016-80305P. This work was partially supported by Comunidad de Madrid (S2017/BMD 3867 RENIM-CM) and cofinanced by the European Structural andInvestment Fund. M.M. is supported by the Miguel Servet Program (CP 19/014, Fundación de Investigación del Hospital 12 de Octubre). J.O., E.G., and R.R-D. are supported by Juan de la Cierva (FJCI2017-33855, IJC2018-036850-I, and IJCI2017-31399, respectively). Support was also provided by Ministerio de Ciencia e Innovación grants (RTI2018-099246-B-I00 to J.M.R. and PI18/00543 to J.F.N.) and Comunidad de Madrid and Fondo Social Europeo funds (AORTASANA-CM; B2017/BMD-3676 to A.M.B., A.F., and J.M.R.). J.M.R. was also funded by Fundacion La Caixa (HR18-00068) and the Marfan Foundation (USA). J.M.R. and J.L.M.V. were also funded by Centro de Investigación Biomedica en Red Enfermedades Cardiovasculares of Ministerio de Ciencia e Innovación (CB16/11/00264). J.F.N. was funded by Ministerio de Economía y Competitividad (PI18/00543) and Centro de Investigación Biomedica en Red Enfermedades Cardiovasculares (CB16/11/00264), and was cofunded by Fondo Europeo de Desarrollo Regional.
NO Instituto de Salud Carlos III
NO European Commission
NO Comunidad de Madrid
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 9 abr 2025