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

ABSTRACT: 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.

SUBMITTER: Solsona-Vilarrasa E

PROVIDER: S-EPMC6526464 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Solsona-Vilarrasa Estel E Fucho Raquel R Torres Sandra S Nuñez Susana S Nuño-Lámbarri Natalia N Enrich Carlos C García-Ruiz Carmen C Fernández-Checa José C JC

Redox biology 20190509

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 increas ...[more]

PMID: 31108462

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Project description:Alzheimer's disease (AD), the most common cause of sporadic dementia of in adults, shows increased risk of occurrence with aging and is destined to become a major sociomedical tragedy over the next few decades. Although likely complex in origin, sporadic AD is characterized by a progressive and stereotyped neuropathology with aggregated protein deposition (esp beta amyloid (BA) and hyperphosphorylated tau (P-tau)) and neuronal degeneration. To date, prevention of BA synthesis or immune-mediated removal of BA has failed to alter AD progression. Development and testing of P-tau therapeutics are a work in progress. AD brain tissues show multiple system deficits, including loss of respiratory capacity. In the present study there were no differences in mitochondrial mass between AD and CTL samples. We examined mitochondrial preparations of postmortem AD and CTL frontal cortex for relative levels of individual respiratory protein complexes by Western immunoblotting. ANOVA revealed deficiencies of all respiratory complex subunits in AD; post-ANOVA t-testing revealed significant differences in levels of subunits for complexes II, III, and V, borderline significance for subunit of complex IV, and no difference for subunit of complex I. We also examined mitochondrial extracts with blue-native gel electrophoresis combined with immunoblotting for subunits of complexes I and III to search for "respiratory supercomplexes" (RSC's). We found that levels of RSC's did not differ between AD and CTL samples. Mitochondrial preparations from end-stage AD brain tissue showed loss of individual ATP-producing respiration subunits but preservation of levels of assembled respiratory subunits into RSC's. Possible explanations include insufficient sensitivity of our method of RSC detection to find loss of individual subunits, or normal levels of RSC's in AD brain mitochondria coupled with decreased levels of nonassembled respiratory complex subunits. Disease-altering therapies of early AD could include stimulation of mitochondrial biogenesis to overcome loss of respiratory subunits.

Dataset Information

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

Publications

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

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