Since the pioneering discovery of heat shock proteins in
by Ferruccio Ritossa in 1960s, a long and exciting journey has been undertaken by molecular biologists and researchers worldwide. Not only ...lower organisms like worms, yeast, amoeba, and flies but also eukaryotes share common cellular response signals to stressful conditions that can arise from the outside but also from the inside. Moreover, extraordinary interplay between nucleus and subcellular organelles, and between different organelles, like mitochondria and the endoplasmic reticulum called mitochondria-associated endoplasmic reticulum membranes (MAMs), are involved in aging and human diseases like obesity, diabetes, inflammation, neurodegeneration, autoimmune diseases, atherosclerosis, and cancer. Actually, we know that to hit abnormal proteostasis and lipid exchanges in the endoplasmic reticulum is crucial to best guide effective therapies or discover new drugs. Indeed, restoration or impairment of endoplasmic reticulum shape and function lead to cellular homeostasis by autophagy or to final death generally by apoptosis or pyroptosis. This Special Issue collects current valuable articles or reviews on cellular stress research and each contribution opens a new window for further studies and hypothesis. I hope that readers interested in this fascinating topic may be stimulated to know more and more.
Prolonging the healthy life span and limiting neurological illness are imperative goals in gerontology. Age-related neurodegeneration is progressive and leads to severe diseases affecting motility, ...memory, cognitive function, and social life. To date, no effective treatments are available for neurodegeneration and irreversible neuronal loss. Bioactive phytochemicals could represent a natural alternative to ensure active aging and slow onset of neurodegenerative diseases in elderly patients. Autophagy or macroautophagy is an evolutionarily conserved clearing process that is needed to remove aggregate-prone proteins and organelles in neurons and glia. It also is crucial in synaptic plasticity. Aberrant autophagy has a key role in aging and neurodegeneration. Recent evidence indicates that polyphenols like resveratrol and curcumin, flavonoids, like quercetin, polyamine, like spermidine and sugars, like trehalose, limit brain damage i
n vitro
and
in vivo
. Their common mechanism of action leads to restoration of efficient autophagy by dismantling misfolded proteins and dysfunctional mitochondria. This review focuses on the role of dietary phytochemicals as modulators of autophagy to fight Alzheimer’s and Parkinson’s diseases, fronto-temporal dementia, amyotrophic lateral sclerosis, and psychiatric disorders. Currently, most studies have involved
in vitro
or preclinical animal models, and the therapeutic use of phytochemicals in patients remains limited.
Mitophagy in Human Diseases Doblado, Laura; Lueck, Claudia; Rey, Claudia ...
International journal of molecular sciences,
04/2021, Letnik:
22, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role ...during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.
Skeletal muscle disorders are dramatically increasing with human aging with enormous sanitary costs and impact on the quality of life. Preventive and therapeutic tools to limit onset and progression ...of muscle frailty include nutrition and physical training. Melatonin, the indole produced at nighttime in pineal and extra-pineal sites in mammalians, has recognized anti-aging, anti-inflammatory, and anti-oxidant properties. Mitochondria are the favorite target of melatonin, which maintains them efficiently, scavenging free radicals and reducing oxidative damage. Here, we discuss the most recent evidence of dietary melatonin efficacy in age-related skeletal muscle disorders in cellular, preclinical, and clinical studies. Furthermore, we analyze the emerging impact of melatonin on physical activity. Finally, we consider the newest evidence of the gut-muscle axis and the influence of exercise and probably melatonin on the microbiota. In our opinion, this review reinforces the relevance of melatonin as a safe nutraceutical that limits skeletal muscle frailty and prolongs physical performance.
Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been ...found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice (
) orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and
mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that
mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in
mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation.
A hypercaloric fatty diet predisposes an individual to metabolic syndrome and cardiovascular complications. Sirtuin1 (SIRT1) belongs to the class III histone deacetylase family and sustains ...anabolism, mitochondrial biogenesis, and fat distribution. Epididymal white adipose tissue (eWAT) is involved in inflammation, whilst interscapular brown adipose tissue (iBAT) drives metabolism in obese rodents. Melatonin, a pineal indoleamine, acting as a SIRT1 modulator, may alleviate cardiometabolic damage. In the present study, we morphologically characterized the heart, eWAT, and iBAT in male heterozygous SIRT1
mice (HET mice) on a high-fat diet (60%E lard) versus a standard rodent diet (8.5% E fat) and drinking melatonin (10 mg/kg) for 16 weeks. Wild-type (WT) male C57Bl6/J mice were similarly fed for comparison. Cardiomyocyte fibrosis and endoplasmic reticulum (ER) stress response worsened in HET mice on a high-fat diet vs. other groups. Lipid peroxidation, ER, and mitochondrial stress were assessed by 4 hydroxy-2-nonenal (4HNE), glucose-regulated protein78 (GRP78), CCAA/enhancer-binding protein homologous protein (CHOP), heat shock protein 60 (HSP60), and mitofusin2 immunostainings. Ultrastructural analysis indicated the prevalence of atypical inter-myofibrillar mitochondria with short, misaligned cristae in HET mice on a lard diet despite melatonin supplementation. Abnormal eWAT adipocytes, crown-like inflammatory structures, tumor necrosis factor alpha (TNFα), and iBAT whitening characterized HET mice on a hypercaloric fatty diet and were maintained after melatonin supply. All these data suggest that melatonin's mechanism of action is strictly linked to full SIRT1 expression, which is required for the exhibition of effective antioxidant and anti-inflammatory properties.
Autophagy dysregulation is commonplace in the pathogenesis of several invalidating diseases, such as musculoskeletal diseases. Polyamines, as spermidine and spermine, are small aliphatic cations ...essential for cell growth and differentiation, with multiple antioxidant, anti-inflammatory, and anti-apoptotic effects. Remarkably, they are emerging as natural autophagy regulators with strong anti-aging effects. Polyamine levels were significantly altered in the skeletal muscles of aged animals. Therefore, supplementation of spermine and spermidine may be important to prevent or treat muscle atrophy. Recent in vitro and in vivo experimental studies indicate that spermidine reverses dysfunctional autophagy and stimulates mitophagy in muscles and heart, preventing senescence. Physical exercise, as polyamines, regulates skeletal muscle mass inducing proper autophagy and mitophagy. This narrative review focuses on the latest evidence regarding the efficacy of polyamines and exercise as autophagy inducers, alone or coupled, in alleviating sarcopenia and aging-dependent musculoskeletal diseases. A comprehensive description of overall autophagic steps in muscle, polyamine metabolic pathways, and effects of the role of autophagy inducers played by both polyamines and exercise has been presented. Although literature shows few data in regard to this controversial topic, interesting effects on muscle atrophy in murine models have emerged when the two "autophagy-inducers" were combined. We hope these findings, with caution, can encourage researchers to continue investigating in this direction. In particular, if these novel insights could be confirmed in further in vivo and clinical studies, and the two synergic treatments could be optimized in terms of dose and duration, then polyamine supplementation and physical exercise might have a clinical potential in sarcopenia, and more importantly, implications for a healthy lifestyle in the elderly population.
Obesity is a common risk factor for non-alcoholic fatty liver disease (NAFLD). Currently, there are no specific treatments against NAFLD. Thus, examining any molecule with potential benefits against ...this condition emerged melatonin as a molecule that influences metabolic dysfunctions. The aim of this study was to determine whether melatonin would function against NAFDL, studying morphological, ultrastuctural and metabolic markers that characterize the liver of ob/ob mice.
Lean and ob/ob mice were supplemented with melatonin in the drinking water for 8 weeks. Histology and stereology were performed to assess hepatic steatosis and glycogen deposition. Ultrastructural features of mitochondria, endoplasmic reticulum (ER) and their juxtapositions were evaluated in livers of all experimental groups. Furthermore, hepatic distribution and expression of markers of ER and mitochondria (calnexin, ATP sintase β, GRP78 and CHOP) and metabolic dysfunction (RPB4, β-catenin) and cellular longevity (SIRT1) were analyzed.
Melatonin significantly reduced glycemia, identified also by a decrease of hepatic RBP4 expression, reversed macrosteatosis in microsteatosis at the hepatic pericentral zone, enlarged ER-mitochondrial distance and ameliorated the morphology and organization of these organelles in ob/ob mouse liver. Furthermore, in ob/ob mice, calnexin and ATP synthase β were partially restored, GRP78 and CHOP decreased in periportal and midzonal hepatocytes and β-catenin expression was, in part, restored in peripheral membranes of hepatocytes. Melatonin supplementation to ob/ob mice improves hepatic morphological, ultrastructural and metabolic damage that occurs as a result of NAFLD.
Melatonin may be a potential adjuvant treatment to limit NAFLD and its progression into irreversible complications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity is a common and complex health problem, which impacts crucial organs; it is also considered an independent risk factor for chronic kidney disease. Few studies have analyzed the consequence of ...obesity in the renal proximal convoluted tubules, which are the major tubules involved in reabsorptive processes. For optimal performance of the kidney, energy is primarily provided by mitochondria. Melatonin, an indoleamine and antioxidant, has been identified in mitochondria, and there is considerable evidence regarding its essential role in the prevention of oxidative mitochondrial damage. In this study we evaluated the mechanism(s) of mitochondrial alterations in an animal model of obesity (ob/ob mice) and describe the beneficial effects of melatonin treatment on mitochondrial morphology and dynamics as influenced by mitofusin-2 and the intrinsic apoptotic cascade. Melatonin dissolved in 1% ethanol was added to the drinking water from postnatal week 5-13; the calculated dose of melatonin intake was 100 mg/kg body weight/day. Compared to control mice, obesity-related morphological alterations were apparent in the proximal tubules which contained round mitochondria with irregular, short cristae and cells with elevated apoptotic index. Melatonin supplementation in obese mice changed mitochondria shape and cristae organization of proximal tubules, enhanced mitofusin-2 expression, which in turn modulated the progression of the mitochondria-driven intrinsic apoptotic pathway. These changes possibly aid in reducing renal failure. The melatonin-mediated changes indicate its potential protective use against renal morphological damage and dysfunction associated with obesity and metabolic disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lead (Pb) is an environmental oncogenic metal that induces immunotoxicity and anaemia. Emerging evidence has linked Pb toxicity with endoplasmic reticulum-driven apoptosis and autophagy. ...Glucose-regulated protein of 78 kDa (Grp78 or binding immunoglobulin protein (BiP)), a master endoplasmic reticulum chaperone, drives macrophage activation and regulates protein folding and calcium flux in response to heavy metals. The spleen may be involved in Pb poisoning due to its crucial role in erythrocatheresis and immune response, although there are no data to support this theory. Here, we found haematic and histopathological changes in the spleen of mice exposed to medium doses of Pb acetate (200 ppm–1 mM) in drinking water for 45 days. Pb deposition was also detected in organs such as the liver, kidney, brain, bone, blood and faeces, indicating an accumulation of this metal despite relatively short exposure time. Blood Pb content (BBL) reached 21.6 μg/dL; echinocytes and poikilocytes were found in Pb smears of treated group. Inside the spleen, higher Fe(II) and Fe(III) deposits inside macrophages were observed. Grp78 immunostaining, weakly expressed in spleen cells of control mice, after Pb exposure was specifically restricted to macrophages and megakaryocytes of the marginal zone of red pulp. Furthermore, Pb exposure induced superoxide dismutase 1 (SOD1) expression, cleaved caspase-3 and p62/SQSTM1, consistent with oxidative stress, apoptosis and dysregulated autophagy in spleen compartments. We suggest that even at a middle dose, oral Pb intake induces oxidant iron deposition in the spleen and that this may trigger sustained Grp78 redistribution to cells, thus leading to oxidative and autophagy dysfunction as early local reactions to this dangerous metal.
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