Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

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dc.contributor.author	Solsona Vilarrasa, Estel
dc.contributor.author	Fucho Salvador, Raquel
dc.contributor.author	Torres, Sandra
dc.contributor.author	Nuñez, Susana
dc.contributor.author	Nuño-Lámbarri, Natalia
dc.contributor.author	Enrich Bastús, Carles
dc.contributor.author	García-Ruiz, Carmen
dc.contributor.author	Fernández-Checa Torres, José Carlos
dc.date	2020-01-24T19:01:25Z
dc.date	2020-01-24T19:01:25Z
dc.date	2019-06
dc.date	2020-01-24T19:01:26Z
dc.identifier	2213-2317
dc.identifier	http://hdl.handle.net/2445/148700
dc.identifier	694857
dc.identifier.uri	http://hdl.handle.net/2445/148700
dc.description	Mitochondrial cholesterol accumulation is a hallmark of alcoholic and non-alcoholic fatty liver diseases and impairs the function of specific solute carriers through changes in membrane physical properties. However, its impact on mitochondrial respiration and organization of respiratory supercomplexes has not been determined so far. Here we fed mice a cholesterol-enriched diet (HC) supplemented with sodium cholate to examine the effect of cholesterol in mitochondrial function. HC feeding increased liver cholesterol content, which downregulated Srebp2 and Hmgcr expression, while sodium cholate administration decreased Cyp7a1 and Cyp8b1 mRNA levels, suggesting the downregulation of bile acid synthesis through the classical pathway. HC-fed mice exhibited increased expression of Stard1 and Mln64 and enhanced mitochondrial free cholesterol levels (2-3 fold), leading to decreased membrane fluidity. Mitochondria from HC-fed mice displayed increased cholesterol loading in both outer and inner mitochondrial membranes. Cholesterol loading decreased complex I and complex II-driven state 3 respiration and mitochondrial membrane potential. Decreased respiratory and uncoupling control ratio from complex I was also observed after in situ enrichment of mouse liver mitochondria with cholesterol or enantiomer cholesterol, the mirror image of natural cholesterol. Moreover, in vivo cholesterol loading decreased the level of complex III2 and the assembly of respiratory supercomplexes I1+III2+IV and I1+III2. Moreover, HC feeding caused oxidative stress and mitochondrial GSH (mGSH) depletion, which translated in hepatic steatosis and liver injury, effects that were rescued by replenishing mGSH with GSH ethyl ester. Overall, mitochondrial cholesterol accumulation disrupts mitochondrial functional performance and the organization of respiratory supercomplexes assembly, which can contribute to oxidative stress and liver injury.
dc.format	13 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	Elsevier B.V.
dc.relation	Reproducció del document publicat a: https://doi.org/10.1016/j.redox.2019.101214
dc.relation	Redox Biology, 2019, vol. 24, p. 101214
dc.relation	https://doi.org/10.1016/j.redox.2019.101214
dc.rights	cc-by-nc-nd (c) Elsevier B.V., 2019
dc.rights	http://creativecommons.org/licenses/by-nc-nd/3.0/es
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Colesterol
dc.subject	Malalties del fetge
dc.subject	Fetge
dc.subject	Cholesterol
dc.subject	Liver diseases
dc.subject	Liver
dc.title	Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/acceptedVersion

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