Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity.

A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.

Mitochondrial depolarization can initiate reversal activity of ATP synthase, depleting ATP by its hydrolysis. We have recently shown that increased ATP hydrolysis contributes to ATP depletion leading to a maladaptation in mitochondrial disorders, where maximal hydrolytic capacity per CV content is increasing. However, despite its importance, ATP hydrolysis is not a commonly studied parameter because of the limitations of the currently available methods.

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.

The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV.

Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.

Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans.

Regulation of hepatic coenzyme Q biosynthesis by dietary omega-3 polyunsaturated fatty acids.

Dietary fats are important for human health, yet it is not fully understood how different fats affect various health problems. Although polyunsaturated fatty acids (PUFAs) are generally considered as highly oxidizable, those of the n-3 series can ameliorate the risk of many age-related disorders. Coenzyme Q (CoQ) is both an essential component of the mitochondrial electron transport chain and the only lipid-soluble antioxidant that animal cells can synthesize.

Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors.

Coenzyme Q (ubiquinone or CoQ) is a conserved polyprenylated lipid essential for mitochondrial respiration. CoQ is composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. A classic pathway leading to CoQ biosynthesis employs 4-hydroxybenzoic acid (4HB).

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.

Mitochondrial carriers (MCs) mediate the passage of small molecules across the inner mitochondrial membrane (IMM), enabling regulated crosstalk between compartmentalized reactions. Despite MCs representing the largest family of solute carriers in mammals, most have not been subjected to a comprehensive investigation, limiting our understanding of their metabolic contributions. Here, we functionally characterize SFXN1, a member of the non-canonical, sideroflexin family.

Metabolism of the Flavonol Kaempferol in Kidney Cells Liberates the B-ring to Enter Coenzyme Q Biosynthesis.

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an important antioxidant present in all cellular membranes. CoQ deficiencies are frequent in aging and in age-related diseases, and current treatments are limited to CoQ supplementation. Strategies that rely on CoQ supplementation suffer from poor uptake and trafficking of this very hydrophobic molecule.

Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae.

Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation.

ADCK4 Deficiency Destabilizes the Coenzyme Q Complex, Which Is Rescued by 2,4-Dihydroxybenzoic Acid Treatment.

Background: Mutations in (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q (CoQ) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from mutations are not well understood, largely because the function of ADCK4 remains unknown.

Methods: To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific, -knockout mouse model and a human podocyte cell line featuring knockout of .

deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10.

Coenzyme Q (Q ) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast , deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q The yeast deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q at an impaired rate. Thus, Coq10 is required for the function of Q in respiration and as an antioxidant and is believed to chaperone Q from its site of synthesis to the respiratory complexes.

The Endoplasmic Reticulum-Mitochondria Encounter Structure Complex Coordinates Coenzyme Q Biosynthesis.

Loss of the endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) complex that resides in contact sites between the yeast ER and mitochondria leads to impaired respiration; however, the reason for that is not clear. We find that in null mutants, there is an increase in the level of mRNAs encoding for biosynthetic enzymes of coenzyme Q (CoQ), an essential electron carrier of the mitochondrial respiratory chain. We show that the mega complexes involved in CoQ biosynthesis (CoQ synthomes) are destabilized in ERMES mutants.

Coenzyme Q deficiencies: pathways in yeast and humans.

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. mutants provide a powerful model for our understanding of CoQ biosynthesis.

Ubiquinol Effects on Antiphospholipid Syndrome Prothrombotic Profile: A Randomized, Placebo-Controlled Trial.

Objective: Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients' prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q [Q]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial.

Kaempferol increases levels of coenzyme Q in kidney cells and serves as a biosynthetic ring precursor.

Coenzyme Q (Q) is a lipid-soluble antioxidant essential in cellular physiology. Patients with Q deficiencies, with few exceptions, seldom respond to treatment. Current therapies rely on dietary supplementation with Q, but due to its highly lipophilic nature, Q is difficult to absorb by tissues and cells.

Olive Oil and the Hallmarks of Aging.

Aging is a multifactorial and tissue-specific process involving diverse alterations regarded as the "hallmarks of aging", which include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Virtually all these hallmarks are targeted by dietary olive oil, particularly by virgin olive oil, since many of its beneficial effects can be accounted not only for the monounsaturated nature of its predominant fatty acid (oleic acid), but also for the bioactivity of its minor compounds, which can act on cells though both direct and indirect mechanisms due to their ability to modulate gene expression. Among the minor constituents of virgin olive oil, secoiridoids stand out for their capacity to modulate many pathways that are relevant for the aging process.

The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice.

The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice.

Mitochondrial ultrastructure and markers of dynamics in hepatocytes from aged, calorie restricted mice fed with different dietary fats.

In this paper we analyzed changes in hepatocyte mitochondrial mass and ultrastructure as well as in mitochondrial markers of fission/fusion and biogenesis in mice subjected to 40% calorie restriction (CR) for 18 months versus ad libitum-fed controls. Animals subjected to CR were separated into three groups with different dietary fats: soybean oil (also in controls), fish oil and lard. Therefore, the effect of the dietary fat under CR was studied as well.