The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism

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dc.contributor.authorParedes, F.
dc.contributor.authorWilliams, H.
dc.contributor.authorLiu, X.
dc.contributor.authorHolden, C.
dc.contributor.authorBogan, B.
dc.contributor.authorWang, Y.
dc.contributor.authorCrotty, K.
dc.contributor.authorYeligar, S.
dc.contributor.authorElorza, A.
dc.contributor.authorLin, Zh.
dc.contributor.authorRezvan, A.
dc.contributor.authorSan Martin, A.
dc.date.accessioned2024-09-11T17:24:31Z
dc.date.available2024-09-11T17:24:31Z
dc.date.issued2024-07
dc.descriptionTEXTO COMPLETO EN INGLÉS
dc.description.abstractVascular smooth muscle cells (VSMCs), known for their remarkable lifelong phenotypic plasticity, play a pivotal role in vascular pathologies through their ability to transition between different phenotypes. Our group discovered that the deficiency of the mitochondrial protein Poldip2 induces VSMC differentiation both in vivo and in vitro. Further comprehensive biochemical investigations revealed Poldip2's specific interaction with the mitochondrial ATPase caseinolytic protease chaperone subunit X (CLPX), which is the regulatory subunit for the caseinolytic protease proteolytic subunit (ClpP) that forms part of the ClpXP complex – a proteasome-like protease evolutionarily conserved from bacteria to humans. This interaction limits the protease's activity, and reduced Poldip2 levels lead to ClpXP complex activation. This finding prompted the hypothesis that ClpXP complex activity within the mitochondria may regulate the VSMC phenotype. Employing gain-of-function and loss-of-function strategies, we demonstrated that ClpXP activity significantly influences the VSMC phenotype. Notably, both genetic and pharmacological activation of ClpXP inhibits VSMC plasticity and fosters a quiescent, differentiated, and anti-inflammatory VSMC phenotype. The pharmacological activation of ClpP using TIC10, currently in phase III clinical trials for cancer, successfully replicates this phenotype both in vitro and in vivo and markedly reduces aneurysm development in a mouse model of elastase-induced aortic aneurysms. Our mechanistic exploration indicates that ClpP activation regulates the VSMC phenotype by modifying the cellular NAD+/NADH ratio and activating Sirtuin 1. Our findings reveal the crucial role of mitochondrial proteostasis in the regulation of the VSMC phenotype and propose the ClpP protease as a novel, actionable target for manipulating the VSMC phenotype.
dc.description.urihttps://www-sciencedirect-com.recursosbiblioteca.unab.cl/science/article/pii/S2213231724001812
dc.identifier.citationRedox Biology, Volume 73 , July 2024, 103203
dc.identifier.doihttps://doi.org/10.1016/j.redox.2024.103203
dc.identifier.issn2213-2317
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/60097
dc.language.isoen
dc.publisherElsevier
dc.rights.licenseAttribution-NonCommercial 4.0 International
dc.subjectVascular smooth mucle cell
dc.subjectVasculature
dc.subjectClppClpXP complex
dc.subjectMitochondria
dc.subjectMetabolism
dc.subjectNAD
dc.subject+Sirtuin 1
dc.subjectVSMC
dc.subjectTIC10
dc.subjectAneurysms
dc.titleThe mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism
dc.typeArtículo
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