NAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This ...improved understanding of NAD+ metabolism revived interest in NAD+-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.
•Adaptive cellular metabolism relies on NAD+ to mediate energy signaling•NAD+ therapeutics is showing its potential to treat disease•Metabolic syndrome, cancer, and aging all involve NAD+ signaling
Auwerx and colleagues review how alterations in energy status mediate cellular metabolic changes through NAD+ signaling events and discuss therapeutic opportunities with NAD+ precursors, and inhibitors of NAD+ consumers, for the treatment of metabolic diseases, including obesity, diabetes, neurodegeneration and aging.
The importance of mitochondria in energy metabolism, signal transduction and aging in post-mitotic tissues has been well established. Recently, the crucial role of mitochondrial-linked signaling in ...stem cell function has come to light and the importance of mitochondria in mediating stem cell activity is becoming increasingly recognized. Despite the fact that many stem cells exhibit low mitochondrial content and a reliance on mitochondrial-independent glycolytic metabolism for energy, accumulating evidence has implicated the importance of mitochondrial function in stem cell activation, fate decisions and defense against senescence. In this Review, we discuss the recent advances that link mitochondrial metabolism, homeostasis, stress responses, and dynamics to stem cell function, particularly in the context of disease and aging. This Review will also highlight some recent progress in mitochondrial therapeutics that may present attractive strategies for improving stem cell function as a basis for regenerative medicine and healthy aging.
Repairing Mitochondrial Dysfunction in Disease Sorrentino, Vincenzo; Menzies, Keir J; Auwerx, Johan
Annual review of pharmacology and toxicology,
01/2018, Letnik:
58, Številka:
1
Journal Article
Recenzirano
Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on ...cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review.
Reversible acetylation was initially described as an epigenetic mechanism regulating DNA accessibility. Since then, this process has emerged as a controller of histone and nonhistone acetylation that ...integrates key physiological processes such as metabolism, circadian rhythm and cell cycle, along with gene regulation in various organisms. The widespread and reversible nature of acetylation also revitalized interest in the mechanisms that regulate lysine acetyltransferases (KATs) and deacetylases (KDACs) in health and disease. Changes in protein or histone acetylation are especially relevant for many common diseases including obesity, diabetes mellitus, neurodegenerative diseases and cancer, as well as for some rare diseases such as mitochondrial diseases and lipodystrophies. In this Review, we examine the role of reversible acetylation in metabolic control and how changes in levels of metabolites or cofactors, including nicotinamide adenine dinucleotide, nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or β-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status to adaptive cellular and organismal homeostasis.
Equine metabolic syndrome (EMS) is a widely recognized collection of risk factors for endocrinopathic laminitis. The most important of these risk factors is insulin dysregulation (ID). Clinicians and ...horse owners must recognize the presence of these risk factors so that they can be targeted and controlled to reduce the risk of laminitis attacks. Diagnosis of EMS is based partly on the horse's history and clinical examination findings, and partly on laboratory testing. Several choices of test exist which examine different facets of ID and other related metabolic disturbances. EMS is controlled mainly by dietary strategies and exercise programs that aim to improve insulin regulation and decrease obesity where present. In some cases, pharmacologic aids might be useful. Management of an EMS case is a long‐term strategy requiring diligence and discipline by the horse's carer and support and guidance from their veterinarians.
We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the ...therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.
Display omitted
•Inhibition of poly(ADP-ribose) polymerases (PARPs) enhances endurance performance•Inhibition of PARPs improves mitochondrial function in skeletal muscle•Parp-1 correlates with energy expenditure in heterogeneous mouse populations•Genetic and acquired mitochondrial defects can be rescued by PARP inhibition
Pirinen et al. show that long-term pharmacological poly(ADP-ribose) polymerase (PARP) inhibition enhances muscle mitochondrial function and fitness in mice. PARP inhibitors also improve genetic or acquired mitochondrial dysfunction in worms and human cells, highlighting their therapeutic use for muscle dysfunction associated with defective mitochondrial function.
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of ...cellular nicotinamide adenine dinucleotide (NAD⁺) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD⁺ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmdmdx/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD⁺ may reprogram dysfunctional SCs and improve life span in mammals.
We report our finding that by exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd‐catalyzed alkyne carbohalogenation can be achieved. This operationally ...simple method uses the bulky Pd/Q‐Phos combination and allows access to tetrasubstituted vinyl halides from the corresponding aryl chlorides, bromides, and iodides. Steric effects in the substrate play a key role by promoting C sp 2‐halogen reductive elimination and enabling catalytic turnover. Through a reversible oxidative addition mechanism, a thermodynamically driven isomerization reaction is observed at elevated temperatures. Thus by changing the reaction temperature, both stereoisomers of the reaction become readily accessible.
Bulk makes it E–Z: By exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd‐catalyzed alkyne carbohalogenation can be realized. This reaction provides access to tetrasubstituted vinyl halides from the corresponding aryl halides.
Summary
Background
Certain individuals appear to be predisposed to recurrent pasture‐associated laminitis. Previous studies have predominantly investigated risk factors only after disease occurrence.
...Objectives
To investigate risk factors for pasture‐associated laminitis prior to disease occurrence.
Study design
Prospective cohort study.
Methods
Non‐laminitic ponies aged ≥7 years were recruited. Body condition score (BCS), height, weight, crest height and thickness were measured and an overnight dexamethasone suppression test performed. Plasma or serum adiponectin, leptin, triglyceride, basal insulin, insulin post‐dexamethasone, insulin‐like growth factor 1 (IGF‐1), IGF binding protein 1 (IGFBP‐1), IGFBP‐3, C‐reactive protein, von Willebrand's factor, soluble E‐selectin and P‐selectin concentrations were assayed. Follow‐up data were obtained from owners annually for 3 years to ascertain occurrences of veterinarian‐diagnosed pasture‐associated laminitis. Data were analysed by multivariate logistic regression. Receiver operating characteristic (ROC) curves analysis was performed for significant risk factors and cut‐off values determined.
Results
A total of 446 animals with a median (interquartile range) age of 15 (10–20) years were recruited. Of these, 50.4% were mares and 49.6% were geldings. The most common breeds were Welsh (36.4%), Shetland (17.0%) and cob (9.4%). Overall, 72.2% of animals were overweight/obese (BCS 7–9/9), 27.3% were of ideal weight (BCS 4–6/9) and 0.5% were underweight (BCS 1–3/9). After 1, 2 and 3 years, respectively, 18 (4.0%), 30 (6.7%) and 44 (9.9%) animals were reported to have had laminitis. Plasma adiponectin, and serum basal (insulin) and (insulin) post‐dexamethasone levels were significantly (P ≤ 0.05) associated with laminitis occurrence cumulatively after 1, 2 and 3 years. Use of the area under the ROC curves to distinguish animals that did and did not develop laminitis showed good (basal insulin after 1 year), fair (all others) or poor (insulin post‐dexamethasone) levels of accuracy.
Main limitations
Animals were evaluated at a single time point and biomarkers were assayed using single assays.
Conclusions
Risk factors for future laminitis prior to disease occurrence include low plasma adiponectin and high serum basal insulin or insulin post‐dexamethasone concentrations.
Background
Quantifying risk factors for laminitis development requires improvement.
Objectives
To identify the most useful physical examination, metabolic and management factors to predict laminitis ...development in client‐owned, nonlaminitic ponies.
Study design
Prospective cohort study.
Methods
Physical examination, metabolic and management data were collected from a pony cohort 6 monthly for up to 4 years. Ponies were monitored for the development of laminitis. Metabolic data included basal plasma concentrations of ACTH (ACTH), adiponectin (adiponectin), triglycerides and glucose. Serum insulin concentrations (insulin) were measured in the unfasted basal state (insulinT0) and 60 minutes (insulinT60) after administration of corn syrup (0.3ml/kg). Separate multivariable Cox proportional‐hazards models were developed for physical, management/signalment and metabolic data and later combined into two final models. Low‐, medium‐ and high‐laminitis risk categories were defined based on basal or T60 insulin.
Results
Overall, 374 ponies (age 5‐32 years) and 891 pony‐years were included in the main analysis. Laminitis incidence (95% confidence interval (CI)) was 4.8 (3.5‐6.5) cases/100 pony‐years. Laminitis development was associated with numerous univariable factors. Significant (P < .05) factors retained in the final multivariable models included insulinT0, insulinT60, adiponectin and divergent hoof growth. ACTH was not independently associated with laminitis. Based on InsulinT0, low‐ (<21.6 µIU/ml), medium‐ (21.6‐45.2 µIU/ml) and high‐risk (>45.2 µIU/ml) categories encompassed 70, 20 and 10% of the population and had estimated 4‐year laminitis incidences (95%CI) of 6 (2‐9)%, 22 (10‐33)% and 69 (48‐82)% respectively. Based on InsulinT60 the low‐ (<53.4 µIU/ml), medium‐ (53.4‐153 µIU/ml) and high‐risk (≥153 µIU/ml) categories comprised 60, 30 and 10% of the population and had estimated 4‐year laminitis incidences (95%CI) of 3 (0‐6)%, 20 (10‐29)% and 73 (52‐84)% respectively.
Main limitations
Results may not apply to different insulin assays, geographical regions, breeds or management types.
Conclusions
InsulinT0 or insulinT60 best quantify the risk of future laminitis development in nonlaminitic ponies.
Resumo
Contexto
A quantificação dos fatores de risco para o desenvolvimento de laminite requere mais estudos.
Objetivos
Identificar os fatores de exame físico, níveis metabólicos e de manejo mais úteis para predizer o desenvolvimento de laminite em pôneis não laminíticos de proprietários privados.
Delineamento do estudo
Coorte prospectivo.
Metodologia
Exame físico e dados metabólicos e de manejo foram coletados de um coorte de pôneis a cada seis meses por um máximo de quatro anos. Os pôneis foram monitorados para o desenvolvimento de laminite. Dados metabólicos incluíram: concentração basal de ACTH (ACTH), adiponectina (adiponectina), triglicérides e glicose. A concentração sérica de insulina (insulina) foi mensurada no estado basal sem jejum (insulinaT0) e 60 minutos (insulinaT60) após a administração de xarope de milho (0.3ml/kg). Modelos separados de riscos proporcionais de Cox multivariável foram desenvolvidos para dados de exame físico, manejo/identificação dos animais e metabólicos, que depois foram combinados em dois modelos finais. As categorias para o risco de desenvolvimento de laminite foram classificadas como baixa, média e alta, levando em consideração o nível basal ou T60 de insulina.
Resultados
374 pôneis (idades entre 5 e 32 anos) e um total de 891 anos acumulados foram incluídos na análise. A incidência de laminite (95% de intervalo de confiança (IC)) foi 4.8 (3.5‐6.5) casos/100 anos. O desenvolvimento de laminite foi associado com inúmeros fatores invariáveis. Os fatores significantes (p<0.05) retidos no modelo de análise multivariável final foram: insulina T0, insulina T60, adiponectina, e crescimento de casco divergente. ACTH não foi independentemente associado com laminite. Baseado nas categorias de insulina T0, as categorias de baixo (<21.6 µIU/ml), médio (21.6‐45.2 µIU/ml) e alto (>45.2 µIU/ml) risco foram compostas por 70, 20 e 10% da população e tiveram uma estimativa de 4 anos de incidência de laminite (95% CI) de 6 (2‐9)%, 22 (10‐33)% e 69 (48‐82%), respectivamente. Baseado na insulina T60, as categorias de risco baixa (<53.4 µIU/ml), média (53.4‐153 µIU/ml) e alta (≥153 µIU/ml) foram compostas por 60, 30 e 10% da população e tiveram uma estimativa de 4 anos de incidência (95% CI) de 3 (0‐6)%, 20 (10‐29)% e 73 (52‐84)%, respectivamente.
Principais limitações
Esses resultados podem não ser aplicáveis com outras metodologias de mensuração de insulina, e outras regiões geográficas, raças ou tipos de manejo.
Conclusões
Insulina T0 ou insulina T60 são os fatores que melhor quantificam o risco de futuro desenvolvimento de laminite em pôneis não laminíticos.
PDF
