Zinc is an essential element for all forms of life, and one in every ten human proteins is a zinc protein. Zinc has catalytic, structural and signalling functions and its correct homeostasis affects ...many cellular processes. Zinc deficiency leads to detrimental consequences, especially in tissues with high demand such as skeletal muscle. Zinc cellular homeostasis is tightly regulated by different transport and buffer protein systems. Specifically, in skeletal muscle, zinc has been found to affect myogenesis and muscle regeneration due to its effects on muscle cell activation, proliferation and differentiation. In relation to skeletal muscle, exercise has been shown to modulate zinc serum and urinary levels and could directly affect cellular zinc transport. The oxidative stress induced by exercise may provide the basis for the mild zinc deficiency observed in athletes and could have severe consequences on health and sport performance. Proteostasis is induced during exercise and zinc plays an essential role in several of the associated pathways.
•Zinc deficiency could be a crucial issue in sport performance for athletes.•Exercise could modulate zinc serum and cellular homeostasis.•Zinc is part of proteostatic systems critical during exercise.
Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the ...most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.
Mitochondria are key in the metabolism of aerobic organisms and in ageing progression and age-related diseases. Mitochondria are essential for obtaining ATP from glucose and fatty acids but also in ...many other essential functions in cells including aminoacids metabolism, pyridine synthesis, phospholipid modifications and calcium regulation. On the other hand, the activity of mitochondria is also the principal source of reactive oxygen species in cells. Ageing and chronic age-related diseases are associated with the deregulation of cell metabolism and dysfunction of mitochondria. Cell metabolism is controlled by three major nutritional sensors: mTOR, AMPK and Sirtuins. These factors control mitochondrial biogenesis and dynamics by regulating fusion, fission and turnover through mito- and autophagy. A complex interaction between the activity of these nutritional sensors, mitochondrial biogenesis rate and dynamics exists and affect ageing, age-related diseases including metabolic disease. Further, mitochondria maintain a constant communication with nucleus modulating gene expression and modifying epigenetics. In this review we highlight the importance of mitochondria in ageing and the repercussion in the progression of age-related diseases and metabolic disease.
Regulation of myogenic gene expression Vicente-García, Cristina; Hernández-Camacho, Juan Diego; Carvajal, Jaime J.
Experimental cell research,
10/2022, Letnik:
419, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Skeletal muscle development and regeneration is governed by the combined action of Myf5, MyoD, Mrf4 and MyoG, also known as the myogenic regulatory factors (MRFs). These transcription factors are ...expressed in a highly spatio-temporal restricted manner, ensuring the significant functional and metabolic diversity observed between the different muscle groups. In this review, we will discuss the multiple layers of regulation that contribute to the control of the exquisite expression patterns of the MRFs in particular, and of myogenic genes in general. We will highlight all major regulatory processes that play a role in myogenesis: from those that modulate chromatin status and transcription competence, such as DNA methylation, histone modification, chromatin remodeling, or non-coding RNAs, to those that control transcript and protein processing and modification, such as alternative splicing, polyadenylation, other mRNA modifications, or post-translational protein modifications. All these processes are exquisitely and tightly coordinated to ensure the proper activation, maintenance and termination of the myogenic process.
Clinical update on metabolic syndrome Hernández-Camacho, Juan Diego; Hernández-Camacho, Miguel
Revista Española de Nutrición Humana y Dietética,
01/2017, Letnik:
21, Številka:
4
Journal Article
Odprti dostop
Metabolic syndrome has been defined as a global issue since it affects a lot of people. Numerous factors are involved in metabolic syndrome development. It has been described that metabolic syndrome ...has negative consequences on health. Consequently, a lot of treatments have been proposed to palliate it such as drugs, surgery or life style changes where nutritional habits have shown to be an important point in its management. The current study reviews the literature existing about the actual epidemiology of metabolic syndrome, the components involucrate in its appearance and progression, the clinical consequences of metabolic syndrome and the nutritional strategies reported in its remission. A bibliographic search in PubMed and Medline was performed to identify eligible studies. Authors obtained that metabolic syndrome is present in population from developed and undeveloped areas in a huge scale. Environmental and genetic elements are involucrate in metabolic syndrome development. Metabolic syndrome exponentially increased risk of cardiovascular disease, some types of cancers, diabetes mellitus type 2, sleep disturbances, etc. Nutritional treatments play a crucial role in metabolic syndrome prevention, treatment and recovery.
Resveratrol (RSV) is a bioactive natural molecule that induces antioxidant activity and increases protection against oxidative damage. RSV could be used to mitigate damages associated to metabolic ...diseases and aging. Particularly, RSV regulates different aspects of mitochondrial metabolism. However, no information is available about the effects of RSV on Coenzyme Q (CoQ), a central component in the mitochondrial electron transport chain. Here, we report for the first time that RSV modulates
genes and parameters associated to metabolic syndrome in mice. Mice fed with high fat diet (HFD) presented a higher weight gain, triglycerides (TGs) and cholesterol levels while RSV reverted TGs to control level but not weight or cholesterol. HFD induced a decrease of
gene mRNA level, whereas RSV reversed this decrease in most of the
genes. However, RSV did not show effect on CoQ
, CoQ
and total CoQ levels, neither in CoQ-dependent antioxidant enzymes. HFD influenced mitochondrial dynamics and mitophagy markers. RSV modulated the levels of PINK1 and PARKIN and their ratio, indicating modulation of mitophagy. In summary, we report that RSV influences some of the metabolic adaptations of HFD affecting mitochondrial physiology while also regulates
gene expression levels in a process that can be associated with mitochondrial dynamics and turnover.
Abstract The protein encoded by COQ7 is required for CoQ 10 synthesis in humans, hydroxylating 3‐demethoxyubiquinol (DMQ 10 ) in the second to last steps of the pathway. COQ7 mutations lead to a ...primary CoQ 10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ 10 primary deficiency caused by five mutations in COQ7 , three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ 10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ 10 deficiency. However, transcriptional analysis of mitochondria‐associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.
Alpha-1 antitrypsin (AAT) is an acute-phase glycoprotein encoded by the SERPINA1 gene. This allele has a codominant expression and Alpha-1 antitrypsin deficiency (AATD) is caused by the inheritance ...of two affected alleles. The spectrum of the disease depends on the variants and environmental and biological factors. This study aimed to divulge Costa Rica's experience in diagnosing AATD using biochemical and molecular approaches in patients referred to this center between 2014 and 2021.
: Forty-three patients (20 males and 23 females) were analyzed.
Serum AAT concentrations were quantified by turbidometry (SPIN200E, ®SPINREACT). Protein electrophoresis and phenotyping isoelectric electrophoresis were performed on the HYDRASYS 2 SCAN FOCUSING (SEBIA).
Sanger sequencing of the SERPINA1 coding regions (NM_000295.5) was performed in 16 patients with rare electrophoretic patterns or MM phenotype with low AAT concentration.
In 43 probands, we found an AAT mean value of 60.7mg/dl and eight different electrophoretic patterns. Most of our affected patients had an MZ or ZZ phenotype. Table 1 shows the main phenotypes and genotypes of our patients (N=25 patients); how some of them share the same electrophoretic pattern; and finally, the correlation between clinical severity and the biochemical phenotype. Our lab found two variants, one related to null phenotype and the other with uncertain clinical significance (VUS).
:
• This laboratory has developed an efficient and comprehensive algorithm diagnosis for AATD that involves biochemical and molecular tools.
• Genetic analysis has allowed the identification of null variants (Q0Cork and Q0Lisbon).
• AATD affects children and adults, with a broad severity spectrum and different clinical presentations.
• Patients with one affected allele (e.g., PI*MZ, Pi*MS) might show some clinical manifestations.
• Accurate diagnosis is essential for optimal clinical attention and to reduce the diagnostic odyssey.
Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving ...a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.
ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic ...reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous
Adck2
knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either
ad libitum
or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption.
In vitro
differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.
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