bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2022–10–02
seventeen papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
  2. The Ketogenic Diet maintains insulin sensitivity and inhibits lipid accumulation in the liver.
  3. The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.
  4. Function and mechanism of histone β-hydroxybutyrylation in health and disease.
  5. Ketone bodies and the heart.
  6. New insights into cellular links between sodium-glucose cotransporter-2 inhibitors and ketogenesis.
  7. Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.
  8. Dietary Contributions to Metabolic Acidosis.
  9. Interaction of sodium acetate supplementation and dietary fiber level on feeding behavior, digestibility, milk synthesis, and plasma metabolites.
  10. Effects of Endurance Training on Metabolic Enzyme Activity and Transporter Proteins in Skeletal Muscle of Ovariectomized Mice.
  11. FOXO signaling pathway in skeletal muscle atrophy.
  12. TRIM50 promotes NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization.
  13. PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.
  14. NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson's disease.
  15. Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
  16. On the role of ubiquinone in the proton translocation mechanism of respiratory complex I.
  17. Nutritional Aspects of Healthy Aging.
  1. Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2205755119
    Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
    Volha Mezhnina, Oghogho P Ebeigbe, Nikkhil Velingkaar, Allan Poe, Yana Sandlers, Roman V Kondratov.
      Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock-deficient Cry1,2-/- mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.
    Keywords:  aging; caloric restriction; circadian rhythms; fatty acid metabolism; metabolism
    DOI:  https://doi.org/10.1073/pnas.2205755119
  2. J Physiol. 2022 Sep 26.
    The Ketogenic Diet maintains insulin sensitivity and inhibits lipid accumulation in the liver.
    Alexa N King, Nicole M Notaro.
      
    Keywords:  Ketogenic Diet; NAFLD; ceramides; inflammation; insulin resistance
    DOI:  https://doi.org/10.1113/JP283784
  3. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01278-5. [Epub ahead of print]40(13): 111437
    The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.
    Christina Li-Ping Thio, Alan Chuan-Ying Lai, Yu-Tse Ting, Po-Yu Chi, Ya-Jen Chang.
      Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma.
    Keywords:  BHB; CP: Immunology; CP: Metabolism; IL-2; ILC2; allergic asthma; ketogenic diet; mast cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.111437
  4. Front Immunol. 2022 ;13 981285
    Function and mechanism of histone β-hydroxybutyrylation in health and disease.
    Tingting Zhou, Xi Cheng, Yanqiu He, Yumei Xie, Fangyuan Xu, Yong Xu, Wei Huang.
      Histone post-translational modifications (HPTMs) are essential epigenetic mechanisms that affect chromatin-associated nuclear processes without altering the DNA sequence. With the application of mass spectrometry-based proteomics, novel histone lysine acylation, such as propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, and lactoylation have been successively discovered. The emerging diversity of the lysine acylation landscape prompted us to investigate the function and mechanism of these novel HPTMs in health and disease. Recently, it has been reported that β-hydroxybutyrate (BHB), the main component of the ketone body, has various protective roles beyond alternative fuel provision during starvation. Histone lysine β-hydroxybutyrylation (Kbhb) is a novel HPTMs identified by mass spectrometry, which regulates gene transcription in response to carbohydrate restriction or elevated BHB levels in vivo and vitro. Recent studies have shown that histone Kbhb is strongly associated with the pathogenesis of metabolic cardiovascular diseases, kidney diseases, tumors, neuropsychiatric disorders, and metabolic diseases suggesting it has different functions from histone acetylation and methylation. This review focuses on the writers, erasers, sites, and underlying functions of histone Kbhb, providing a glimpse into their complex regulation mechanism.
    Keywords:  epigenetics; gene regulation; histone post-translational modifications; immune; β-hydroxybutyrylation
    DOI:  https://doi.org/10.3389/fimmu.2022.981285
  5. Arch Med Sci Atheroscler Dis. 2021 ;6 e209-e214
    Ketone bodies and the heart.
    Athanasia K Papazafiropoulou, Maximos M Georgopoulos, Nikolaos L Katsilambros.
      Ketone bodies are low chain organic substances with four carbon atoms, with β-hydroxybutyric acid and acetone being the main ketone bodies in blood circulation. Under physiological conditions their levels are low while during conditions of oxidative stress, such as exercise, fasting state and acute illness, ketone body levels are increased. Recent findings have shown that in patients with heart failure their plasma concentration is increased. There is a positive correlation between increased energy metabolism of myocardial cells and the levels of β-hydroxybutyric acid and acetone. Furthermore, it has been hypothesized that the mild ketosis caused by sodium glucose cotransporter 2 inhibitors is one of the possible pathogenetic mechanisms explaining the significant cardiovascular and renal benefits observed in patients with type 2 diabetes treated with these agents. The aim of the present review is to summarize the role of ketone bodies in both normal and pathological conditions, such as heart failure.
    Keywords:  diabetes mellitus; heart failure; ketogenic diet; ketone bodies; β-hydroxybutyric acid
    DOI:  https://doi.org/10.5114/amsad.2021.112475
  6. J Cell Biochem. 2022 Sep 25.
    New insights into cellular links between sodium-glucose cotransporter-2 inhibitors and ketogenesis.
    Habib Yaribeygi, Mina Maleki, Alexandra E Butler, Tannaz Jamialahmadi, Amirhossein Sahebkar.
      Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known. Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.
    Keywords:  beta-oxidation; diabetes mellitus; free fatty acids; gluconeogenesis; ketoacidosis; ketogenesis; ketone body; sodium-glucose cotransporter-2 inhibitors
    DOI:  https://doi.org/10.1002/jcb.30327
  7. Nutr Res. 2022 Aug 12. pii: S0271-5317(22)00073-2. [Epub ahead of print]106 72-84
    Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.
    Sarika Yadav, Ashish Dwivedi, Anurag Tripathi, Amit Kumar Tripathi.
      Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut-brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed.
    Keywords:  Histone deacetylase; Mitochondrial nutrients; Neurodegenerative disease; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.nutres.2022.07.007
  8. Adv Chronic Kidney Dis. 2022 Jul;pii: S1548-5595(22)00068-4. [Epub ahead of print]29(4): 373-380
    Dietary Contributions to Metabolic Acidosis.
    Lynda Frassetto, Thomas Remer, Tanushree Banerjee.
      Eating a net acid-producing diet can produce an "acid stress" of severity proportional to the diet net acid load, as indexed by the steady-state renal net acid excretion rate. Depending on how much acid or base is ingested or produced from endogenous metabolic processes and how well our homeostatic mechanisms can buffer or eliminate the additional acids or bases, we can alter our systemic acid-base balance. With increasing age, the kidney's ability to excrete daily net acid loads declines (a condition similar to that of mild CKD), invoking increased utilization of potential base stores (eg, bone, skeletal muscle) on a daily basis to mitigate the acid accumulation, thereby contributing to development of osteoporosis, loss of muscle mass, and age-related renal insufficiency. Patients suffering from more advanced CKD often present with more severe acid stress or metabolic acidosis, as the kidney can no longer excrete the entire acid load. Alkaline diets based on fruits and vegetables may have a positive effect on long-term preservation of renal function while maintaining nutritional status. This chapter discusses the biochemistry of dietary precursors that affect acid or base production.
    Keywords:  Alkali therapy; Children; Fruits and vegetables; Hypertension; Net acid excretion
    DOI:  https://doi.org/10.1053/j.ackd.2022.03.008
  9. J Dairy Sci. 2022 Sep 26. pii: S0022-0302(22)00546-X. [Epub ahead of print]
    Interaction of sodium acetate supplementation and dietary fiber level on feeding behavior, digestibility, milk synthesis, and plasma metabolites.
    C Matamoros, F Hao, Y Tian, A D Patterson, K J Harvatine.
      Acetate supplementation has been shown to increase milk fat yield in diets with low risk of biohydrogenation-induced milk fat depression. The interaction of acetate supplementation with specific dietary factors that modify rumen fermentation and short-chain fatty acid (FA) synthesis has not been investigated. The objective of this experiment was to determine the effect of acetate supplemented as sodium acetate at 2 dietary fiber levels. Our hypothesis was that acetate would increase milk fat production more in animals fed the low-fiber diet. Twelve lactating multiparous Holstein cows were arranged in a 4 × 4 Latin square design balanced for carryover effects with a 2 × 2 factorial arrangement of dietary fiber level and acetate supplementation with 21-d experimental periods. The high-fiber diet had 32% neutral detergent fiber and 21.8% starch, and the low-fiber diet had 29.5% neutral detergent fiber and 28.7% starch created by substitution of forages predominantly for ground corn grain. Acetate was supplemented in the diet at an average 2.8% of dry matter (DM) to provide approximately 10 mol/d of acetate as anhydrous sodium acetate. Acetate supplementation increased DM intake by 6%, with no effect on meal frequency or size. Furthermore, acetate supplementation slightly increased total-tract apparent DM digestibility and tended to increase organic matter digestibility. Acetate supplementation increased milk fat concentration and yield by 8.6 and 10.5%, respectively, but there was no interaction with dietary fiber. The increase in milk fat synthesis was associated with 46 and 85 g/d increases in the yield of de novo (<16C) and mixed source (16C) FA, respectively, with no changes in yield of preformed FA (>16C). There was a 9% increase in the concentration of milk mixed-source FA and a 7% decrease in milk preformed FA with acetate supplementation, regardless of dietary fiber level. Acetate supplementation also increased the concentrations of plasma acetate and β-hydroxybutyrate, major metabolic substrates for mammary lipogenesis. Overall, acetate supplementation increased milk fat yield regardless of dietary fiber level through an increase mostly caused by an increase in longer-chain de novo FA, suggesting stimulation of mammary lipogenesis. The heightened mammary de novo lipogenesis was supported by an increase in the concentration of metabolic substrates in plasma.
    Keywords:  de novo; lipogenesis; milk fat
    DOI:  https://doi.org/10.3168/jds.2022-21911
  10. Med Sci Sports Exerc. 2022 Sep 28.
    Effects of Endurance Training on Metabolic Enzyme Activity and Transporter Proteins in Skeletal Muscle of Ovariectomized Mice.
    Kenya Takahashi, Yu Kitaoka, Yutaka Matsunaga, Hideo Hatta.
       PURPOSE: Estrogen deficiency or insufficiency can occur under several conditions, leading to negative health outcomes. To establish an effective countermeasure against estrogen loss, we investigated the effects of endurance training on ovariectomy (OVX)-induced metabolic disturbances.
    METHODS: Female ICR mice underwent OVX or sham operations. On day 7 of recovery, the mice were randomized to remain either sedentary or undergo 5 weeks of treadmill running (15-20 m/min, 60 min, 5 days/week). During week 5 of the training, all animals performed a treadmill running test (15 m/min, 60 min).
    RESULTS: Following the experimental period, OVX resulted in greater gains in body mass, fat mass, and triglyceride content in the gastrocnemius muscle. OVX enhanced phosphofructokinase activity in the plantaris muscle and decreased lactate dehydrogenase (LDH) activity in the plantaris and soleus muscles. OVX decreased the protein content of NDUFB8, a mitochondrial respiratory chain subunit, but did not decrease the activities of other mitochondrial proteins or enzymes. Endurance training significantly enhanced mitochondrial enzyme activity and protein content in the skeletal muscles. While OVX increased the respiratory exchange ratio during the treadmill running test, and post-exercise blood lactate levels, endurance training normalized these parameters.
    CONCLUSIONS: The present findings suggest that endurance training is a viable strategy to counteract the negative metabolic consequences in hypoestrogenism.
    DOI:  https://doi.org/10.1249/MSS.0000000000003045
  11. Am J Pathol. 2022 Sep 26. pii: S0002-9440(22)00286-3. [Epub ahead of print]
    FOXO signaling pathway in skeletal muscle atrophy.
    Kun Chen, Peng Gao, Zongchao Li, Aonan Dai, Ming Yang, Siyu Chen, Jingyue Su, Zhenhan Deng, Liangjun Li.
      Skeletal muscle atrophy is the consequence of protein degradation exceeding protein synthesis due to disease, aging and physical inactivity. Patients with skeletal muscle atrophy have decreased muscle mass and fiber cross-sectional area, thereby suffering reduced survival quality and motor function. The forkhead box O (FOXO) signaling pathway plays an important role in the pathogenesis of skeletal muscle atrophy by regulating E3 ubiquitin ligases and some autophagy factors. However, the mechanism of FOXO signaling pathway leading to skeletal muscle atrophy is still unclear and needs to be further explored. The development of treatment strategies for skeletal muscle atrophy has been a thorny clinical problem. FOXO-targeted therapy to treat skeletal muscle atrophy is a promising approach, and an increasing number of relevant studies have been reported. In this paper, we reviewed the mechanism and therapeutic targets of the FOXO signaling pathway mediating skeletal muscle atrophy, and provided some new ideas for the clinical treatment of this condition.
    Keywords:  Atrogin-1; FOXO signaling pathway; IGF-1/PI3K/AKT signaling pathway; MuRF-1; skeletal muscle atrophy
    DOI:  https://doi.org/10.1016/j.ajpath.2022.09.003
  12. EMBO Rep. 2022 Sep 30. e54569
    TRIM50 promotes NLRP3 inflammasome activation by directly inducing NLRP3 oligomerization.
    Yueke Lin, Xiaoting Lv, Caiyu Sun, Yanlin Sun, Min Yang, Dapeng Ma, Weiqiang Jing, Yunxue Zhao, Yeping Cheng, Haocheng Xuan, Lihui Han.
      Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.
    Keywords:  NLRP3 inflammasome; TRIM50; inflammation; oligomerization; ubiquitination
    DOI:  https://doi.org/10.15252/embr.202154569
  13. Sci Rep. 2022 Sep 26. 12(1): 16028
    PGC-1β maintains mitochondrial metabolism and restrains inflammatory gene expression.
    Hannah Guak, Ryan D Sheldon, Ian Beddows, Alexandra Vander Ark, Matthew J Weiland, Hui Shen, Russell G Jones, Julie St-Pierre, Eric H Ma, Connie M Krawczyk.
      Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-β (IFN-β), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1β (PGC-1β), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-β, when OXPHOS is maintained. We examined the role of PGC-1β in bioenergetic metabolism of DCs and found that PGC-1β deficiency indeed impairs their mitochondrial respiration. PGC-1β-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1β deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-β treatment. Loss of PGC-1β in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1β is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs.
    DOI:  https://doi.org/10.1038/s41598-022-20215-6
  14. Eur J Pharmacol. 2022 Sep 24. pii: S0014-2999(22)00561-1. [Epub ahead of print] 175300
    NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson's disease.
    Mayuri Khot, Anika Sood, Kamatham Pushpa Tryphena, Sabiya Khan, Saurabh Srivastava, Shashi Bala Singh, Dharmendra Kumar Khatri.
      Parkinson's disease (PD) is a common neurodegenerative condition for which no approved treatment exists to prevent collective neuronal death. There is ample evidence that mitochondrial dysfunction, reactive oxygen species (ROS), and associated caspase activity underlie the pathology observed. Neurons rely on mitochondrial activity since they have such high energy consumption. Therefore, it is not surprising that mitochondrial alterations favour neuronal degeneration. In particular, mitochondrial dysregulation contributes to PD, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Also, it is known that inflammatory cytokine-mediated neuroinflammation is the key pathogenic mechanism in neuronal loss. In recent years, the research has focussed on mitochondria being the platform for nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome activation. Mitochondrial dysfunction and NLRP3 activation are emerging as critical players in inducing and sustaining neuroinflammation. Moreover, mitochondrial-derived ROS and mitochondrial DNA (mtDNA) could serve as the priming signal for forming inflammasome complexes responsible for the activation, maturation, and release of pro-inflammatory cytokines, including interleukin-1(IL-1) and interleukin-18 (IL-18). The current review takes a more comprehensive approach to elucidating the link between mitochondrial dysfunction and aberrant NLRP3 activation in PD. In addition, we focus on some inhibitors of NLRP3 inflammatory pathways to alleviate the progression of PD.
    Keywords:  Cytokines; Mitochondria; NLRP3; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175300
  15. Geroscience. 2022 Sep 26.
    Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age.
    Colleen S Deane, Bethan E Phillips, Craig R G Willis, Daniel J Wilkinson, Ken Smith, Nahoko Higashitani, John P Williams, Nathaniel J Szewczyk, Philip J Atherton, Atsushi Higashitani, Timothy Etheridge.
      Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass (P > 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14-3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.
    Keywords:  Ageing; Hub protein; Network analysis; Phosphoproteome; Proteomics
    DOI:  https://doi.org/10.1007/s11357-022-00658-5
  16. FEBS Lett. 2022 Sep 30.
    On the role of ubiquinone in the proton translocation mechanism of respiratory complex I.
    Mårten Wikström, Amina Djurabekova, Vivek Sharma.
      Complex I converts oxidoreduction energy into a proton electrochemical gradient across the inner mitochondrial or bacterial cell membrane. This gradient is the primary source of energy for aerobic synthesis of ATP. Oxidation of reduced nicotinamide adenine dinucleotide (NADH) by ubiquinone (Q) yields NAD+ and ubiquinol (QH2 ), which is tightly coupled to translocation of four protons from the negatively to the positively charged side of the membrane. Electrons from NADH oxidation reach the iron-sulfur centre N2 positioned near the bottom of a tunnel that extends ca. 30Å from the membrane domain into the hydrophilic domain of the complex. The tunnel is occupied by ubiquinone, which can take a distal position near the N2 centre, or proximal positions closer to the membrane. Here, we review important structural, kinetic and thermodynamic properties of ubiquinone that define its role in complex I function. We suggest that this function exceeds that of a mere substrate or electron acceptor, and propose that ubiquinone may be the redox element of complex I coupling electron transfer to proton translocation.
    Keywords:  energy conservation; mitochondria; oxidative phosphorylation; proton pumping
    DOI:  https://doi.org/10.1002/1873-3468.14506
  17. Med Clin North Am. 2022 Sep;pii: S0025-7125(22)00058-X. [Epub ahead of print]106(5): 853-863
    Nutritional Aspects of Healthy Aging.
    Alexander Panda, Sarah L Booth.
      Proper nutrition and healthy eating are key determinants of healthy aging. In older age, energy requirements decrease, yet micronutrient requirements stay the same or increase, which make older adults susceptible to nutrient deficiencies. Therefore, it is important to encourage older adults to consume nutrient-dense foods. Many older adults do not maintain proper hydration, so adequate water intake should also be encouraged. Most older adults have multiple chronic diseases that may influence their dietary intake and nutritional needs. However, currently, our understanding of how individual chronic diseases and their associated treatments influence dietary requirements is limited.
    Keywords:  Aging; Dietary requirements; Healthspan; Nutrition
    DOI:  https://doi.org/10.1016/j.mcna.2022.04.008
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