Ranea-Robles, PabloGalino, JorgeEspinosa Blay, LluísSchlüter, AgathaRuiz, MontserratCalingasan, Noel YlaganVillarroya, FrancescNaudí, AlbaPamplona, ReinaldFerrer, IsidreBeal, M. FlintPortero Otín, ManuelFourcade, StéphanePujol, Aurora, 1968-2022-07-042022Ranea-Robles P, Galino J, Espinosa L, Schlüter A, Ruiz M, Calingasan NY, Villarroya F, Naudí A, Pamplona R, Ferrer I, Beal MF, Portero-Otín M, Fourcade S, Pujol A. Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model. Neuropathol Appl Neurobiol. 2022 Feb;48(1):e12747. DOI: 10.1111/nan.127470305-1846http://hdl.handle.net/10230/53662Aims: Mitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor-interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1- mouse model of X-linked adrenoleukodystrophy (X-ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation. Methods and results: We provide evidence that RIP140 is modulated through a redox-dependent mechanism driven by very long-chain fatty acids (VLCFAs), the levels of which are increased in X-ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X-ALD mouse models. Conclusions: Together, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X-ALD, underscoring its potential as a therapeutic target for X-ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.application/pdfengThis is the peer reviewed version of the following article: Ranea-Robles P, Galino J, Espinosa L, Schlüter A, Ruiz M, Calingasan NY, Villarroya F, Naudí A, Pamplona R, Ferrer I, Beal MF, Portero-Otín M, Fourcade S, Pujol A. Modulation of mitochondrial and inflammatory homeostasis through RIP140 is neuroprotective in an adrenoleukodystrophy mouse model. Neuropathol Appl Neurobiol. 2022 Feb;48(1):e12747. DOI: 10.1111/nan.12747, which has been published in final form at http://dx.doi.org/10.1111/nan.12747. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/nan.12747RIP140AdrenoleukodystrophyMitochondriaNeuroinflammationOxidative stressinfo:eu-repo/semantics/openAccess