In mammals, 24-h rhythms of behaviour and physiology are regulated by the circadian clock. The circadian clock is controlled by a central clock in the brain's suprachiasmatic nucleus (SCN) that ...synchronizes peripheral clocks in peripheral tissues. Clock genes in the SCN are primarily entrained by light. Increasing evidence has shown that peripheral clocks are also regulated by light and hormones independent of the SCN. How the peripheral clocks deal with internal signals is dependent on the relevance of a specific cue to a specific tissue. In different tissues, most genes that are under circadian control are not overlapping, revealing the tissue-specific control of peripheral clocks. We will discuss how different signals control the peripheral clocks in different peripheral tissues, such as the liver, gastrointestinal tract, and pancreas, and discuss the organ-to-organ communication between the peripheral clocks at the molecular level.
•Peripheral clock can regulate synchronization independent of superchiasmatic nucleus (SCN).•We discuss how different signals entrain peripheral circadian clocks in peripheral tissues.•Organ-to-organ communications are involved in entrainment of peripheral circadian clocks.
SignificanceMutations of polycystin-1 (PC1) are the major cause (85% of cases) of autosomal dominant polycystic kidney disease (ADPKD), which is the fourth leading cause of kidney failure. PC1 is ...thought to function as an atypical G protein-coupled receptor, yet the mechanism by which PC1 regulates G-protein signaling remains poorly understood. A significant portion of ADPKD mutations of PC1 encode a protein with defects in maturation or reduced function that may be amenable to functional rescue. In this work, we have combined complementary biochemical and cellular assay experiments and accelerated molecular simulations, which revealed an allosteric transduction pathway in activation of the PC1 C-terminal fragment. Our findings will facilitate future rational drug design efforts targeting the PC1 signaling function.
The development of the foetal heart is driven by increased glucose uptake and activation of mammalian target of rapamycin (mTOR) and hypoxia‐inducible factor‐1α (HIF‐1α), which drives glycolysis. In ...contrast, the healthy adult heart is governed by sirtuin‐1 (SIRT1) and adenosine monophosphate‐activated protein kinase (AMPK), which promote fatty‐acid oxidation and the substantial mitochondrial ATP production required for survival in a high‐workload normoxic environment. During cardiac injury, the heart recapitulates the foetal signalling programme, which (although adaptive in the short term) is highly deleterious if sustained for long periods of time. Prolonged increases in glucose uptake in cardiomyocytes under stress leads to increased flux through the hexosamine biosynthesis pathway; its endproduct – uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) – functions as a critical nutrient surplus sensor. UDP‐GlcNAc drives the post‐translational protein modification known as O‐GlcNAcylation, which rapidly and reversibly modifies thousands of intracellular proteins. Both O‐GlcNAcylation and phosphorylation act at serine/threonine residues, but whereas phosphorylation is regulated by hundreds of specific kinases and phosphatases, O‐GlcNAcylation is regulated by only two enzymes, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), which adds or removes GlcNAc (N‐acetylglucosamine), respectively, from target proteins. Recapitulation of foetal programming in heart failure (regardless of diabetes) is accompanied by marked increases in O‐GlcNAcylation, both experimentally and clinically. Heightened O‐GlcNAcylation in the heart leads to impaired calcium kinetics and contractile derangements, arrhythmias related to activation of voltage‐gated sodium channels and Ca2+/calmodulin‐dependent protein kinase II, mitochondrial dysfunction, and maladaptive hypertrophy, microvascular dysfunction, fibrosis and cardiomyopathy. These deleterious effects can be prevented by suppression of O‐GlcNAcylation, which can be achieved experimentally by upregulation of AMPK and SIRT1 or by pharmacological inhibition of OGT or stimulation of OGA. The effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on the heart are accompanied by reduced O‐GlcNAcylation, and their cytoprotective effects are reportedly abrogated if their action to suppress O‐GlcNAcylation is blocked. Such an action may represent one of the many mechanisms by which enhanced AMPK and SIRT1 signalling following SGLT2 inhibition leads to cardiovascular benefits. These observations, taken collectively, suggest that UDP‐GlcNAc functions as a critical nutrient surplus sensor (which acting in concert with mTOR and HIF‐1α) can promote the development of cardiomyopathy.
Mitochondrial-derived peptides and exercise Woodhead, Jonathan S.T.; Merry, Troy L.
Biochimica et biophysica acta. General subjects,
December 2021, 2021-12-00, 20211201, Letnik:
1865, Številka:
12
Journal Article
Recenzirano
Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise ...training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.
•There is building evidence that acute exercise and exercise training can modulate muscle and plasma MDP levels•Effect of exercise on MDPs appears to be MDP, tissue and exercise mode/duration dependent•MOTS-c treatment improves exercise performance of mice, but appears not to be essential exercise-training induced adaptations•Further work is required to define inter- and intra-tissue targets of MDPs in an exercise context
The incorporation of nanomaterials into electrochemical sensors is an attractive approach towards the improvement of the sensitivity of amperometry and also can provide improved sensor selectivity ...and stability. This review (with 137 references) details the current state of the art and new trends in nanomaterial-based electrochemical sensing of hydrogen peroxide (H
2
O
2
), hydrogen sulfide (H
2
S) and nitric oxide (NO) in cells or released by cells. The article starts with a discussion of the significance of the three analytes, and this is followed by three sections that summarize the electrochemical detection schemes for H
2
O
2
, H
2
S and NO. Each section first summarizes the respective physiological roles, and then reviews electrochemical sensors based on the use of carbon nanomaterials, noble metal nanomaterials, metal oxide nanomaterials, and layered doubled hydroxides. The materials are compiled in three tables along with figures of merit for the various sensors.
Graphical abstract
Nanomaterial-based electrochemical sensors for Reactive oxygen species (H
2
O
2
), Reactive nitrogen species (NO) and Reactive hydrogen sulfide species (H
2
S) inside cells or released by cells.
Aerobic glycolysis has been generally associated with cancer cell proliferation, but fascinating and novel data show that it is also coupled to a series of further cellular functions. In this Mini ...Review, we will discuss some recent findings to illustrate newly defined roles for this process, in particular in non-malignant cells, supporting the idea that metabolism can be considered as an integral part of cellular signaling. Consequently, metabolism should be regarded as a plastic and highly dynamic determinant of a wide range of cellular specific functions.
Cellular signalling cues lead to the initiation of apoptotic pathways and often result in the activation of caspases which in turn cause the generation of proteolytically generated protein fragments ...with new or altered functions. Mounting number of studies reveal that the activity of these proteolytically activated protein fragments can be counteracted via their selective degradation by the N-degron degradation pathways. Here, we investigate the proteolytically generated fragment of the PKC theta kinase, where we demonstrate the first report on the stability of this pro-apoptotic protein fragment. We have determined that the pro-apoptotic cleaved fragment of PKC-theta is unstable in cells because its N-terminal lysine targets it for proteasomal degradation via the N-degron degradation pathway and this degradation is inhibited by mutating the destabilizing N-termini, knockdown of the UBR1 and UBR2 E3 ligases. Tellingly, we demonstrate that the metabolic stabilization of the cleaved fragment of PKC-theta or inhibition of the N-degron degradation augments the apoptosis-inducing effect of staurosporine in Jurkat cells. Notably, we have unveiled that the cleaved fragment of PKC theta, per se, can induce apoptotic cell death in Jurkat T-cell leukemia. Our results expand the functional scope of mammalian N-degron degradation pathways, and support the notion that targeting N-degron degradation machinery may have promising therapeutic implications in cancer cells.
Since its discovery more than a century ago, nicotinamide adenine dinucleotide (NAD+) is recognised as a fascinating cornerstone of cellular metabolism. This ubiquitous energy cofactor plays vital ...roles in metabolic pathways and regulatory processes, a fact emphasised by the essentiality of a balanced NAD+ metabolism for normal plant growth and development. Research on the role of NAD in plants has been predominantly carried out in the model plant Arabidopsis thaliana (Arabidopsis) with emphasis on the redox properties and cellular signalling functions of the metabolite. This review examines the current state of knowledge concerning how NAD can regulate both metabolic pools and gene expression in Arabidopsis. Particular focus is placed on recent studies highlighting the complexity of metabolic regulations involving NAD, more particularly in the mitochondrial compartment, and of signalling roles with respect to interactions with environmental fluctuations most specifically those involving plant immunity.
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•NAD+ is a fascinating cornerstone of plant cellular metabolism.•NAD+ involves a complex network of metabolic and redox regulations in Arabidopsis.•Beside redox properties, NAD+ is important for cell signalling including responses to stress.•NAD+ acts as an integral regulator of immune responses in Arabidopsis.
Summary
The functional link between cell‐surface receptors and intracellular NLR immune receptors is a critical aspect of plant immunity. To establish disease, successful pathogens have evolved ...mechanisms to suppress cell‐surface immune signalling. In response, plants have adapted by evolving NLRs that recognize pathogen effectors involved in this suppression, thereby counteracting their immune‐suppressing function. This ongoing co‐evolutionary struggle has seemingly resulted in intertwined signalling pathways in some plant species, where NLRs form a separate signalling branch downstream of activated cell‐surface receptor complexes essential for full immunity. Understanding these interconnected receptor networks could lead to novel strategies for developing durable disease resistance.
Jiorgos Kourelis is a finalist of the 2023
New Phytologist
Tansley Medal competition for excellence in plant science. See Slater & Dolan (
2023, 240: 2171–2172
) for more details.
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