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.
Discovered in the beginning of the 20th century, nicotinamide adenine dinucleotide (NAD+) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of ...regulatory proteins that include the sirtuin family of NAD+‐dependent protein deacylases, widely recognized regulators of metabolic function and longevity. Altered NAD+ metabolism is associated with aging and many pathological conditions, such as metabolic diseases and disorders of the muscular and neuronal systems. Conversely, increased NAD+ levels have shown to be beneficial in a broad spectrum of diseases. Here, we review the fundamental aspects of NAD+ biochemistry and metabolism and discuss how boosting NAD+ content can help ameliorate mitochondrial homeostasis and as such improve healthspan and lifespan.
As part of our focus series on metabolism, this review discusses the physiological role of NAD+ and the potential therapeutic effects of increasing NAD+ levels.
Mitocellular communication: Shaping health and disease Mottis, Adrienne; Herzig, Sébastien; Auwerx, Johan
Science (American Association for the Advancement of Science),
11/2019, Letnik:
366, Številka:
6467
Journal Article
Recenzirano
Odprti dostop
Throughout the animal kingdom, mitochondria are the only organelles that retain their own genome and the transcription and translation machineries that are all essential for energy harvesting. ...Mitochondria have developed a complex communication network, allowing them to stay in tune with cellular needs and nuclear transcriptional programs and to alleviate mitochondrial dysfunction. Here, we review recent findings on the wide array of mechanisms that contribute to these mitocellular communication networks, spanning from well-studied messenger molecules to mitonuclear genetic interactions. Based on these observations and developments, we advocate a broad and inclusive view on mitocellular interactions, which can have profound impacts on physiological, pathological, and evolutionary processes.
Sirtuin 1 (SIRT1) is an evolutionarily conserved NAD(+)-dependent deacetylase that is at the pinnacle of metabolic control, all the way from yeast to humans. SIRT1 senses changes in intracellular ...NAD(+) levels, which reflect energy level, and uses this information to adapt the cellular energy output such that it matches cellular energy requirements. The changes induced by SIRT1 activation are generally (but not exclusively) transcriptional in nature and are related to an increase in mitochondrial metabolism and antioxidant protection. These attractive features have validated SIRT1 as a therapeutic target in the management of metabolic disease and prompted an intensive search to identify pharmacological SIRT1 activators. In this review, we first give an overview of the SIRT1 biology with a particular focus on its role in metabolic control. We then analyze the pros and cons of the current strategies used to activate SIRT1 and explore the emerging evidence indicating that modulation of NAD(+) levels could provide an effective way to achieve such goals.
The AMP-activated protein kinase (AMPK) is a key regulator of catabolic versus anabolic processes. Its properties as an energy sensor allow it to couple the energy status of the cell to the metabolic ...environment. These adaptations not only take place through the acute modulation of key metabolic enzymes via direct phosphorylation, but also through a slower transcriptional adaptative response. The question of how AMPK regulates the expression of a number of gene sets, such as those related to mitochondrial biogenesis, energy production and oxidative protection, is only beginning to be elucidated, and still many questions remain to be answered. In this review we will try to integrate our current knowledge on how AMPK regulates transcription in muscle and liver, which will serve as examples to illustrate the major advances in the field and the key challenges ahead.
Maintenance of the mitochondrial proteome is performed primarily by chaperones, which fold and assemble proteins, and by proteases, which degrade excess damaged proteins. Upon various types of ...mitochondrial stress, triggered genetically or pharmacologically, dysfunction of the proteome is sensed and communicated to the nucleus, where an extensive transcriptional program, aimed to repair the damage, is activated. This feedback loop, termed the mitochondrial unfolded protein response (UPRmt ), synchronizes the activity of the mitochondrial and nuclear genomes and as such ensures the quality of the mitochondrial proteome. Here we review the recent advances in the UPRmt field and discuss its induction, signaling, communication with the other mitochondrial and major cellular regulatory pathways, as well as its potential implications on health and lifespan.
Through epigenetic mechanisms cells integrate environmental stimuli to fine-tune gene expression levels. Mitochondrial function is essential to provide the intermediate metabolites necessary to ...generate and modify epigenetic marks in the nucleus, which in turn can regulate the expression of mitochondrial proteins. In this review we summarize the function of mitochondria in the regulation of epigenetic mechanisms as a new aspect of mitonuclear communication. We focus in particular on the most common epigenetic modifications – histone acetylation and histone and DNA methylation. We also discuss the emerging field of mitochondrial DNA (mtDNA) methylation, whose physiological role remains unknown. Finally, we describe the essential role of some histone modifications in regulating the mitochondrial unfolded protein response (UPRmt ) and the mitochondrial stress-dependent lifespan extension.
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.
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.
Dietary restriction can extend life span in most organisms tested to date, suggesting that mechanisms sensing nutrient and energy availability might regulate longevity. The AMP-activated protein ...kinase (AMPK) has emerged as a key energy sensor with the ability to transcriptionally reprogram the cell and metabolically adapt to external cues. In this review, we will discuss the possible role of AMPK in the beneficial effects of calorie restriction on health and life span.
PDF
