bims-kimdis 2023-08-27 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–08–27
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Low-Calorie Ketogenic Diet: Potential Application in the Treatment of Polycystic Ovary Syndrome in Adolescents.
Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.
Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts.
Popular Dietary Trends' Impact on Athletic Performance: A Critical Analysis Review.
Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.
High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.
Higher mitochondrial oxidative capacity is the primary molecular differentiator in muscle of rats with high and low intrinsic cardiorespiratory fitness.
Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.
Current knowledges in pharmaconutrition: "Ketogenics" in pediatric gliomas.
Point-of-Care Capillary Blood Ketone Measurements and the Prediction of Future Ketoacidosis Risk in Type 1 Diabetes.
NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient.
Obesity enables NLRP3 activation and induces myocardial fibrosis via hyperacetylation of HADHa.
Nod-like receptors in inflammatory arthritis.
Long-chain dicarboxylic acids play a critical role in inducing peroxisomal β-oxidation and hepatic triacylglycerol accumulation.
Decrease in Mouse Skeletal Muscle During Aging is Due to Altered Mitochondrial Networks and the MICOS Complex.
Physical Exercise and Appetite Regulation: New Insights.
Regulation of Mitochondrial Respiration by Hydrogen Sulfide.
Polyether-Ether-Ketone (PEEK) and Its 3D-Printed Quantitate Assessment in Cranial Reconstruction.
Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.
Nicotinic acid attenuates experimental non-alcoholic steatohepatitis by inhibiting the NLRP3 inflammasome/pyroptosis pathway.
Role of Mitochondria-ER Contact Sites in Mitophagy.
The fourth dimension: physiological resilience as an independent determinant of endurance exercise performance.

Nutrients. 2023 Aug 15. pii: 3582. [Epub ahead of print]15(16):

Low-Calorie Ketogenic Diet: Potential Application in the Treatment of Polycystic Ovary Syndrome in Adolescents.

Valeria Calcaterra, Hellas Cena, Francesca Sottotetti, Chiara Hruby, Nagaia Madini, Noemi Zelaschi, Gianvincenzo Zuccotti.

  Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Hyperandrogenism, hyperinsulinism and insulin resistance (IR) are the main drivers of clinical, metabolic and reproductive phenotypes of PCOS. In adolescence, the cornerstones of PCOS treatment are lifestyle and dietary interventions. In particular, the quality and quantity of carbohydrates introduced with the diet play a crucial role in the benefits of diet on PCOS. Recently, the ketogenic diet (KD) has attracted significant interest for the treatment of IR and for the control of carbohydrate metabolism, which has proven to be beneficial for several dysmetabolic conditions, including PCOS. The goal of the KD is to induce a fasting-like metabolism with production of chetonic bodies. Ketosis is a good regulator of calorie intake and mimics the starvation effect in the body, leading to body weight control and consequent metabolism. Additionally, during ketogenesis, insulin receptor sensitivity is also promoted. We proposed a broad overview of the available literature regarding KD indications and considered its metabolic benefits useful for improving PCOS management. The reported data support that a low-calorie ketogenic diet (LCKD) plays a positive role as a regulator of control weight, IR, glucose and lipid homeostasis and hormonal profile. Unfortunately, the evidence concerning the benefits of the very LCKD in adolescents with PCOS and excessive body weight is still numerically scarce. Further studies are necessary to understand whether these effects are due to weight loss or to the nutritional characteristics of this diet. Considering the long-term consequences of PCOS, it is crucial to detect the prospects of nutritional interventions to protect fertility, starting in adolescence.

Keywords:  diet; ketogenic diet; low-calorie ketogenic diet; nutritional intervention; polycystic ovary syndrome; very-low-calorie ketogenic diet

DOI:  https://doi.org/10.3390/nu15163582
J Am Heart Assoc. 2023 Aug 23. e029960

Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.

Sebastian Niezen, Margery A Connelly, Calvin Hirsch, Jorge R Kizer, Maria E Benitez, Scott Minchenberg, Maria Camila Perez-Matos, Zhenghui Gordon Jiang, Kenneth J Mukamal.

  Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; P=0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; P=0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; P=0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.

Keywords:  aging; heart failure; ketone bodies; metabolism; mortality

DOI:  https://doi.org/10.1161/JAHA.123.029960
Metabolites. 2023 Aug 03. pii: 910. [Epub ahead of print]13(8):

Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts.

Luca Catalano, Sepideh Aminzadeh-Gohari, Daniela D Weber, Rodolphe Poupardin, Victoria E Stefan, William J Smiles, Julia Tevini, René G Feichtinger, Sophia Derdak, Martin Bilban, Stefan Bareswill, Markus M Heimesaat, Barbara Kofler.

  Neuroblastoma (NB) is a childhood cancer in which amplification of the MYCN gene is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells rely on both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) for energy production. Previously, we demonstrated that a ketogenic diet (KD) combined with metronomic cyclophosphamide (CP) delayed tumor growth in MYCN-amplified NB xenografts. The anti-diabetic drug metformin (MET) also targets complex I of the OXPHOS system. Therefore, MET-induced disruptions of mitochondrial respiration may enhance the anti-tumor effect of CP when combined with a KD. In this study, we found that MET decreased cell proliferation and mitochondrial respiration in MYCN-amplified NB cell lines, while the combination of KD, MET, and low-dose CP (triple therapy) also reduced tumor growth and improved survival in vivo in MYCN-amplified NB xenografts. Gene ontology enrichment analysis revealed that this triple therapy had the greatest effect on the transcription of genes involved in fatty acid ß-oxidation, which was supported by the increased protein expression of CPT1A, a key mitochondrial fatty acid transporter. We suspect that alterations to ß-oxidation alongside the inhibition of complex I may hamper mitochondrial energy production, thus explaining these augmented anti-tumor effects, suggesting that the combination of MET and KD is an effective adjuvant therapy to CP in MYCN-amplified NB xenografts.

Keywords:  MYCN; ketogenic diet; metformin; neuroblastoma; β-oxidation

DOI:  https://doi.org/10.3390/metabo13080910
Nutrients. 2023 Aug 09. pii: 3511. [Epub ahead of print]15(16):

Popular Dietary Trends' Impact on Athletic Performance: A Critical Analysis Review.

Matthew Kaufman, Chantal Nguyen, Maya Shetty, Marily Oppezzo, Michelle Barrack, Michael Fredericson.

   BACKGROUND: Nutrition fuels optimal performance for athletes. With increased research developments, numerous diets available, and publicity from professional athletes, a review of dietary patterns impact on athletic performance is warranted.
RESULTS: The Mediterranean diet is a low inflammatory diet linked to improved power and muscle endurance and body composition. Ketogenic diets are restrictive of carbohydrates and proteins. Though both show no decrements in weight loss, ketogenic diets, which is a more restrictive form of low-carbohydrate diets, can be more difficult to follow. High-protein and protein-paced versions of low-carbohydrate diets have also shown to benefit athletic performance. Plant-based diets have many variations. Vegans are at risk of micronutrient deficiencies and decreased leucine content, and therefore, decreased muscle protein synthesis. However, the literature has not shown decreases in performance compared to omnivores. Intermittent fasting has many different versions, which may not suit those with comorbidities or specific needs as well as lead to decreases in sprint speed and worsening time to exhaustion.
CONCLUSIONS: This paper critically evaluates the research on diets in relation to athletic performance and details some of the potential risks that should be monitored. No one diet is universally recommend for athletes; however, this article provides the information for athletes to analyze, in conjunction with medical professional counsel, their own diet and consider sustainable changes that can help achieve performance and body habitus goals.

Keywords:  Mediterranean diet; athletes; diets; eating disorders; intermittent fasting; ketogenic; nutrition; plant-based; vegan

DOI:  https://doi.org/10.3390/nu15163511
Antioxidants (Basel). 2023 Aug 17. pii: 1624. [Epub ahead of print]12(8):

Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle.

Alejandra Espinosa, Mariana Casas, Enrique Jaimovich.

  Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.

Keywords:  ATP production; MCU; mitochondria dynamics; mitochondrial network

DOI:  https://doi.org/10.3390/antiox12081624
J Appl Physiol (1985). 2023 Aug 24.

High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.

Gregory N Ruegsegger, Mark W Pataky, Suvyaktha Simha, Matthew M Robinson, Katherine A Klaus, K Sreekumaran Nair.

  This study investigated how different exercise training modalities influence skeletal muscle mitochondrial dynamics. Healthy (average B.M.I.: 25.8 kg/m2), sedentary younger and older participants underwent 12 weeks of supervised high-intensity aerobic interval training (HIIT) (n = 13), resistance training (RT) (n = 14), or combined training (CT) (n = 11). Mitochondrial structure was assessed using transmission electron microscopy (TEM). Regulators of mitochondrial fission and fusion, cardiorespiratory fitness (VO2peak), insulin sensitivity via a hyperinsulinemic-euglycemic clamp, and muscle mitochondrial respiration were assessed. TEM showed increased mitochondrial volume, number, and perimeter following HIIT (p < 0.01), increased mitochondrial number following CT (p < 0.05), and no change in mitochondrial abundance after RT. Increased mitochondrial volume associated with increased mitochondrial respiration and insulin sensitivity following HIIT (p < 0.05). Increased mitochondrial perimeter associated with increased mitochondrial respiration, insulin sensitivity, and VO2peak following HIIT (p < 0.05). No such relationships were observed following CT or RT. OPA1, a regulator of fusion, was increased following HIIT (p < 0.05), while FIS1, a regulator of fission, was decreased following HIIT and CT (p < 0.05). HIIT also increased the ratio of OPA1/FIS1 (p < 0.01), indicative of the balance between fission and fusion, which positively correlated with improvements in respiration, insulin sensitivity, and VO2peak (p <0.05). In conclusion, HIIT induces a larger, more fused mitochondrial tubular network. Changes indicative of increased fusion following HIIT associate with improvements in mitochondrial respiration, insulin sensitivity, and VO2peak supporting the idea that enhanced mitochondrial fusion accompanies notable health benefits of HIIT.

Keywords:  HIIT; aerobic exercise; fission; fusion; mitochondria

DOI:  https://doi.org/10.1152/japplphysiol.00405.2023
Mol Metab. 2023 Aug 23. pii: S2212-8778(23)00127-8. [Epub ahead of print] 101793

Higher mitochondrial oxidative capacity is the primary molecular differentiator in muscle of rats with high and low intrinsic cardiorespiratory fitness.

Johanna Y Fleischman, Françoise Van den Bergh, Nicole L Collins, Madelyn Bowers, Daniel A Beard, Charles F Burant.

   OBJECTIVE: Cardiorespiratory fitness (CRF) is tightly linked with health and longevity and is implicated in metabolic flexibility and substrate metabolism. The high capacity runner (HCR) and low capacity runner (LCR) rat lines are a genetically heterogeneous rat model selected and bred for CRF that reflect CRF in humans by exhibiting differences in nutrient handling. This study aims to differentiate the intrinsic substrate preference of the HCR compared to LCR rats to better understand the intersection of mitochondrial respiration and intrinsic CRF.
METHODS: We performed bulk skeletal muscle RNA-Sequencing on male and female HCR and LCR rats and assessed the effect of rat line on mitochondrial gene expression pathways using the MitoCarta3.0 database. In a separate cohort of rats, mitochondria were isolated from skeletal and cardiac muscle and maximal oxidation rates were measured using an Oroboros O2k when provided either pyruvate or fatty acid substrates.
RESULTS: The expression of mitochondrial genes are significantly upregulated in HCR skeletal muscle in both male and female rats. In respirometry experiments, fatty acid oxidative capacities were greater in HCR compared to LCR, and male compared to female rats, as a function of both mitochondrial quality and mitochondrial density. This effect was greater in the skeletal muscle than in the heart. Pyruvate oxidation did not differ significantly between lines.
CONCLUSIONS: The capacity for increased fatty acid oxidation in the HCR rat is a result of selection for running capacity and is likely a key contributor to the healthy metabolic phenotype of individuals with high CRF.

Keywords:  Mitochondria; cardiorespiratory fitness; metabolism; muscle; oxidation; transcriptomics

DOI:  https://doi.org/10.1016/j.molmet.2023.101793
Mol Cell. 2023 Aug 11. pii: S1097-2765(23)00605-6. [Epub ahead of print]

Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.

Chang Zhao, Heli Wang, Ying Liu, Lin Cheng, Bo Wang, Xiaowen Tian, Hong Fu, Chao Wu, Ziyan Li, Chenglong Shen, Jingjing Yu, Shengyong Yang, Hongbo Hu, Ping Fu, Liang Ma, Chuanxin Wang, Wei Yan, Zhenhua Shao.

  Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating Gi/o protein or β-arrestin effectors. Here, we characterize compound 9n as a Gi-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-Gi pathway. Furthermore, four structures of HCAR2-Gi complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.

Keywords:  BHB; GPCR; HCAR2; allosteric modulation; anti-inflamation; biased allosteric modulator; cryo-EM; ketone body receptor; niacin; structural biology

DOI:  https://doi.org/10.1016/j.molcel.2023.07.030
Front Nutr. 2023 ;10 1222908

Current knowledges in pharmaconutrition: "Ketogenics" in pediatric gliomas.

Nicola Cecchi, Roberta Romanelli, Flavia Ricevuti, Marianna Amitrano, Maria Grazia Carbone, Michele Dinardo, Ernesto Burgio.

  Brain tumors account for 20-25% of pediatric cancers. The most frequent type of brain tumor is Glioma from grade I to grade IV according to the rate of malignancy. Current treatments for gliomas use chemotherapy, radiotherapy, tyrosine kinase inhibitors, monoclonal antibodies and surgery, but each of the treatment strategies has several serious side effects. Therefore, to improve treatment efficacy, it is necessary to tailor therapies to patient and tumor characteristics, using appropriate molecular targets. An increasingly popular strategy is pharmaconutrition, which combines a tailored pharmacological treatment with a diet designed to synergize the effects of drugs. In this review we deal in the molecular mechanisms, the epigenetic effects and modulation of the oxidative stress pathway of ketogenic diets, that underlie its possible role, in the treatment of infantile gliomas, as a complementary approach to conventional cancer therapy.

Keywords:  brain cancer; epigenetic; glioma; ketogenic diet; pediatrics

DOI:  https://doi.org/10.3389/fnut.2023.1222908
Diabetes Care. 2023 Aug 24. pii: dc230840. [Epub ahead of print]

Point-of-Care Capillary Blood Ketone Measurements and the Prediction of Future Ketoacidosis Risk in Type 1 Diabetes.

Cimon Song, Sharon Dhaliwal, Priya Bapat, Daniel Scarr, Abdulmohsen Bakhsh, Dalton Budram, Natasha J Verhoeff, Alanna Weisman, Michael Fralick, Noah M Ivers, David Z I Cherney, George Tomlinson, Leif Erik Lovblom, Doug Mumford, Bruce A Perkins.

OBJECTIVE: Rather than during illness while diabetic ketoacidosis (DKA) is developing, we aimed to determine if levels of routine point-of-care capillary blood ketones could predict future DKA.
RESEARCH DESIGN AND METHODS: We examined previously collected data from placebo-assigned participants in an adjunct-to-insulin medication trial program that included measurement of fasted capillary blood ketone levels twice per week in a 2-month baseline period. The outcome was 6- to 12-month trial-adjudicated DKA.
RESULTS: DKA events occurred in 12 of 484 participants at a median of 105 (interquartile range 43, 199) days. Maximum ketone levels were higher in patient cases compared with in control patients (0.8 [0.6, 1.2] vs. 0.3 [0.2, 0.7] mmol/L; P = 0.002), with a nonparametric area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88). Ketone levels ≥0.8 mmol/L had a sensitivity of 64%, a specificity of 78%, and positive and negative likelihood ratios of 2.9 and 0.5, respectively.
CONCLUSIONS: This proof of concept that routine capillary ketone surveillance can identify individuals at high risk of future DKA implies a role for future technologies including continuous ketone monitoring.

DOI: https://doi.org/10.2337/dc23-0840
Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2303814120

NLRP3 is essential for neutrophil polarization and chemotaxis in response to leukotriene B4 gradient.

Stijn Van Bruggen, Pierre-André Jarrot, Eline Thomas, Casey E Sheehy, Camila M S Silva, Alan Y Hsu, Pierre Cunin, Peter A Nigrovic, Edgar R Gomes, Hongbo R Luo, Clare M Waterman, Denisa D Wagner.

  Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1β and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3-/-) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3-/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.

Keywords:  NLRP3 inflammasome; cell polarization; chemotaxis; neutrophils

DOI:  https://doi.org/10.1073/pnas.2303814120
Diabetes. 2023 Aug 25. pii: db230264. [Epub ahead of print]

Obesity enables NLRP3 activation and induces myocardial fibrosis via hyperacetylation of HADHa.

Yan Deng, Xin Liu, Min Xie, Rui Zhao, Liwei Ji, Kuo Tang, Wei Yang, Wei Ou, Maodi Xie, Tao Li.

Obesity increases the risk of myocardial fibrosis, a pathological change in most heart diseases, but the mechanism has not been fully elucidated. Here, we found that mice with high-fat diet (HFD)-induced obesity had more severe myocardial fibrosis than control mice under normal and ischemia/reperfusion (I/R) conditions, which could be alleviated by neutralizing antibodies against interleukin (IL)-1β and IL-18, downstream products of the nucleotide-binding oligomerization-like receptor protein 3 (NLRP3) inflammasome, and the NLRP3 inhibitor MCC950. Mechanistically, mitochondrial hyperacetylation in obese mouse hearts recruited apoptosis-associated speck-like protein containing a CARD (ASC) to mitochondria and thus facilitated NLRP3 inflammasome assembly. Acetylation of K255 on hydroxyl-CoA dehydrogenase alpha subunit (HADHa) was identified to trigger the mitochondrial localization of ASC. Blockade of HADHa-K255 acetylation downregulated mitochondrial ASC, suppressed the NLRP3 inflammasome and attenuated post-I/R myocardial fibrosis in obese mouse hearts. In obese human patients, the extent of myocardial fibrosis according to T1 MRI was positively correlated with the plasma levels of IL-1β and IL-18, supporting the connection of NLRP3 inflammation to obesity-induced myocardial fibrosis. In conclusion, our study demonstrates that the heart is susceptible to fibrosis under obesity through hyperacetylated HADHa mediated activation of the NLRP3 inflammasome.

DOI: https://doi.org/10.2337/db23-0264
Biomed J. 2023 Aug 18. pii: S2319-4170(23)00092-6. [Epub ahead of print] 100655

Nod-like receptors in inflammatory arthritis.

Sahib Singh Madahar, Alita Gideon, Ali A Abdul-Sater.

  Nod-like receptors (NLRs) are innate immune receptors that play a key role in sensing components from pathogens and from damaged cells or organelles. NLRs form signaling complexes that can lead to activation of transcription factors or effector caspases - by means of inflammasome activation - culminating in promoting inflammation. An increasing body of research supports the role of NLRs in driving pathogenesis of inflammatory arthritis, a collection of diseases that include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and pediatric arthritis. In this review, we briefly discuss the main drivers of inflammatory arthritis diseases and dive into the evidence for - and against - various NLRs in driving these diseases. We also review the studies examining the use of NLR and inflammasome inhibitors as potential therapies for inflammatory arthritis.

Keywords:  Ankylosing Spondylitis; Gout; Nod-like Receptors; Pediatric Arthritis; Psoriatic Arthritis; Rheumatoid Arthritis

DOI:  https://doi.org/10.1016/j.bj.2023.100655
J Biol Chem. 2023 Aug 18. pii: S0021-9258(23)02202-0. [Epub ahead of print] 105174

Long-chain dicarboxylic acids play a critical role in inducing peroxisomal β-oxidation and hepatic triacylglycerol accumulation.

Wei Zhang, Lina Zhang, Haoya Yao, Yaoqing Wang, Xiao Zhang, Lin Shang, Xiaocui Chen, Jia Zeng.

  Recent studies provide evidence that peroxisomal β-oxidation negatively regulates mitochondrial fatty acid oxidation, and induction of peroxisomal β-oxidation causes hepatic lipid accumulation. However, whether there exists a triggering mechanism inducing peroxisomal β-oxidation is not clear. Long-chain dicarboxylic acids are the product of mono fatty acids subjected to ω-oxidation, and both fatty acids ω-oxidation and peroxisomal β-oxidation are induced under ketogenic conditions, indicating there might be a crosstalk between. Here, we revealed that administration of long-chain dicarboxylic acids strongly induces peroxisomal fatty acids β-oxidation and causes hepatic steatosis in mice through the metabolites acetyl-CoA and hydrogen peroxide. Under ketogenic conditions, upregulation of fatty acids ω-oxidation resulted in increased generation of long-chain dicarboxylic acids and induction of peroxisomal β-oxidation, which causes hepatic accumulation of lipid droplets in animals. Inhibition of fatty acids ω-oxidation reduced long-chain dicarboxylic acids formation and significantly lowered peroxisomal β-oxidation and improved hepatic steatosis. Our results suggest that endogenous long-chain dicarboxylic acids act as triggering molecules inducing peroxisomal β-oxidation and hepatic triacylglycerol deposition. Targeting fatty acids ω-oxidation might be an effective pathway in treating fatty liver and related metabolic diseases through regulating peroxisomal β-oxidation.

Keywords:  dicarboxylic acids; hepatic steatosis; mitochondria; peroxisomes; ω-oxidation

DOI:  https://doi.org/10.1016/j.jbc.2023.105174
Microsc Microanal. 2023 Jul 22. 29(Supplement_1): 1199-1200

Decrease in Mouse Skeletal Muscle During Aging is Due to Altered Mitochondrial Networks and the MICOS Complex.

Zer Vue, Edgar Garza-Lopez, Kit Neikirk, Larry Vang, Antentor Hinton.

DOI: https://doi.org/10.1093/micmic/ozad067.617
Biomolecules. 2023 Jul 27. pii: 1170. [Epub ahead of print]13(8):

Physical Exercise and Appetite Regulation: New Insights.

Lorenzo Caruso, Enrico Zauli, Mauro Vaccarezza.

  Physical exercise is considered an important physiological intervention able to prevent cardiovascular diseases, obesity, and obesity-related cardiometabolic imbalance. Nevertheless, basic molecular mechanisms that govern the metabolic benefits of physical exercise are poorly understood. Recent data unveil new mechanisms that potentially explain the link between exercise, feeding suppression, and obesity.

Keywords:  L-Lactate; appetite; obesity; physical exercise

DOI:  https://doi.org/10.3390/biom13081170
Antioxidants (Basel). 2023 Aug 20. pii: 1644. [Epub ahead of print]12(8):

Regulation of Mitochondrial Respiration by Hydrogen Sulfide.

Dandan Huang, Guangqin Jing, Shuhua Zhu.

  Hydrogen sulfide (H2S), the third gasotransmitter, has positive roles in animals and plants. Mitochondria are the source and the target of H2S and the regulatory hub in metabolism, stress, and disease. Mitochondrial bioenergetics is a vital process that produces ATP and provides energy to support the physiological and biochemical processes. H2S regulates mitochondrial bioenergetic functions and mitochondrial oxidative phosphorylation. The article summarizes the recent knowledge of the chemical and biological characteristics, the mitochondrial biosynthesis of H2S, and the regulatory effects of H2S on the tricarboxylic acid cycle and the mitochondrial respiratory chain complexes. The roles of H2S on the tricarboxylic acid cycle and mitochondrial respiratory complexes in mammals have been widely studied. The biological function of H2S is now a hot topic in plants. Mitochondria are also vital organelles regulating plant processes. The regulation of H2S in plant mitochondrial functions is gaining more and more attention. This paper mainly summarizes the current knowledge on the regulatory effects of H2S on the tricarboxylic acid cycle (TCA) and the mitochondrial respiratory chain. A study of the roles of H2S in mitochondrial respiration in plants to elucidate the botanical function of H2S in plants would be highly desirable.

Keywords:  hydrogen sulfide; mitochondria; mitochondrial respiratory complex; oxidative phosphorylation; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/antiox12081644
J Funct Biomater. 2023 Aug 17. pii: 429. [Epub ahead of print]14(8):

Polyether-Ether-Ketone (PEEK) and Its 3D-Printed Quantitate Assessment in Cranial Reconstruction.

Khaja Moiduddin, Syed Hammad Mian, Sherif Mohammed Elseufy, Hisham Alkhalefah, Sundar Ramalingam, Abdul Sayeed.

  Three-dimensional (3D) printing, medical imaging, and implant design have all advanced significantly in recent years, and these developments may change how modern craniomaxillofacial surgeons use patient data to create tailored treatments. Polyether-ether-ketone (PEEK) is often seen as an attractive option over metal biomaterials in medical uses, but a solid PEEK implant often leads to poor osseointegration and clinical failure. Therefore, the objective of this study is to demonstrate the quantitative assessment of a custom porous PEEK implant for cranial reconstruction and to evaluate its fitting accuracy. The research proposes an efficient process for designing, fabricating, simulating, and inspecting a customized porous PEEK implant. In this study, a CT scan is utilized in conjunction with a mirrored reconstruction technique to produce a skull implant. In order to foster cell proliferation, the implant is modified into a porous structure. The implant's strength and stability are examined using finite element analysis. Fused filament fabrication (FFF) is utilized to fabricate the porous PEEK implants, and 3D scanning is used to test its fitting accuracy. The results of the biomechanical analysis indicate that the highest stress observed was approximately 61.92 MPa, which is comparatively low when compared with the yield strength and tensile strength of the material. The implant fitting analysis demonstrates that the implant's variance from the normal skull is less than 0.4436 mm, which is rather low given the delicate anatomy of the area. The results of the study demonstrate the implant's endurance while also increasing the patient's cosmetic value.

Keywords:  3D printing; biomechanical analysis; cranial defects; fitting analysis; polyether-ether-ketone; porous implants

DOI:  https://doi.org/10.3390/jfb14080429
Ageing Res Rev. 2023 Aug 23. pii: S1568-1637(23)00197-6. [Epub ahead of print] 102038

Mitochondrial Transfer Between Cell Crosstalk - An Emerging Role in Mitochondrial Quality Control.

Yi Liu, Tinglv Fu, Guorui Li, Boyang Li, Guoqing Luo, Ning Li, Qing Geng.

  Intercellular signaling and component conduction are essential for multicellular organisms' homeostasis, and mitochondrial transcellular transport is a key example of such cellular component exchange. In physiological situations, mitochondrial transfer is linked with biological development, energy coordination, and clearance of harmful components, remarkably playing important roles in maintaining mitochondrial quality. Mitochondria are engaged in many critical biological activities, like oxidative metabolism and biomolecular synthesis, and are exclusively prone to malfunction in pathological processes. Importantly, severe mitochondrial damage will further amplify the defects in the mitochondrial quality control system, which will mobilize more active mitochondrial transfer, replenish exogenous healthy mitochondria, and remove endogenous damaged mitochondria to facilitate disease outcomes. This review explores intercellular mitochondrial transport in cells, its role in cellular mitochondrial quality control, and the linking mechanisms in cellular crosstalk. We also describe advances in therapeutic strategies for diseases that target mitochondrial transfer.

Keywords:  cell crosstalk; intercellular mitochondrial transfer; mitochondrial quality control; therapy

DOI:  https://doi.org/10.1016/j.arr.2023.102038
Biochem Pharmacol. 2023 Aug 19. pii: S0006-2952(23)00353-2. [Epub ahead of print] 115762

Nicotinic acid attenuates experimental non-alcoholic steatohepatitis by inhibiting the NLRP3 inflammasome/pyroptosis pathway.

Irina Cardoso-Lezama, Miguel Á Fuentes-Figueroa, Erika Ramos-Tovar, Linda Vanessa Márquez-Quiroga, Arturo Ortiz-Fernández, Eduardo E Vargas-Pozada, Jaime Arellanes-Robledo, Víctor Tsutsumi, Pablo Muriel.

  Non-alcoholic steatohepatitis (NASH) is a global public health concern that may progress into fibrosis, cirrhosis, and liver cancer, with limited curative treatment options. While the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is closely linked to NASH progression, nicotinic acid (NA), a vitamin used for the treatment of dyslipidemia, is an emerging pharmaceutical treatment for hepatic steatosis and fibrosis. Here, we investigated pharmacological effects of NA on experimental NASH and whether NLRP3 inflammasome/pyroptosis inhibition is an associated mechanism of action. Rats were fed a high-fat sucrose diet supplemented with cholesterol and a low dose of CCl4. NA significantly reduced inflammation by decreasing the protein levels of tumor necrosis factor-alpha and nuclear factor kappa B. Moreover, NA inhibited the formation of NLRP3- apoptosis-associated speck-like protein containing caspase recruitment domain-Caspase-1, decreasing interleukin-1beta, interleukin-18, and gasdermin D protein. In addition, NA reduced tumor growth factor-beta, alpha-smooth muscle actin, and hepatic levels of collagen-1, consequently decreasing extracellular matrix synthesis. Our results indicate that NA can inhibit NASH progression and encourage further basic and clinical studies on the use of NA for the treatment of human NASH.

Keywords:  Cirrhosis; Liver disease; Nicotinic acid; Non-alcoholic steatohepatitis

DOI:  https://doi.org/10.1016/j.bcp.2023.115762
Biomolecules. 2023 Jul 31. pii: 1198. [Epub ahead of print]13(8):

Role of Mitochondria-ER Contact Sites in Mitophagy.

Alina Rühmkorf, Angelika Bettina Harbauer.

  Mitochondria are often referred to as the "powerhouse" of the cell. However, this organelle has many more functions than simply satisfying the cells' metabolic needs. Mitochondria are involved in calcium homeostasis and lipid metabolism, and they also regulate apoptotic processes. Many of these functions require contact with the ER, which is mediated by several tether proteins located on the respective organellar surfaces, enabling the formation of mitochondria-ER contact sites (MERCS). Upon damage, mitochondria produce reactive oxygen species (ROS) that can harm the surrounding cell. To circumvent toxicity and to maintain a functional pool of healthy organelles, damaged and excess mitochondria can be targeted for degradation via mitophagy, a form of selective autophagy. Defects in mitochondria-ER tethers and the accumulation of damaged mitochondria are found in several neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, which argues that the interplay between the two organelles is vital for neuronal health. This review provides an overview of the different mechanisms of mitochondrial quality control that are implicated with the different mitochondria-ER tether proteins, and also provides a novel perspective on how MERCS are involved in mediating mitophagy upon mitochondrial damage.

Keywords:  mitochondria; mitophagy; organellar contact sites

DOI:  https://doi.org/10.3390/biom13081198
J Physiol. 2023 Aug 22.

The fourth dimension: physiological resilience as an independent determinant of endurance exercise performance.

Andrew M Jones.

  Endurance exercise performance is known to be closely associated with the three physiological pillars of maximal O2 uptake ( V̇O2max$\dot{V}_{{\rm O}_{2}{\rm max}}$ ), economy or efficiency during submaximal exercise, and the fractional utilisation of V̇O2max$\dot{V}_{{\rm O}_{2}{\rm max}}$ (linked to metabolic/lactate threshold phenomena). However, while 'start line' values of these variables are collectively useful in predicting performance in endurance events such as the marathon, it is not widely appreciated that these variables are not static but are prone to significant deterioration as fatiguing endurance exercise proceeds. For example, the 'critical power' (CP), which is a composite of the highest achievable steady-state oxidative metabolic rate and efficiency (O2 cost per watt), may fall by an average of 10% following 2 h of heavy intensity cycle exercise. Even more striking is that the extent of this deterioration displays appreciable inter-individual variability, with changes in CP ranging from <1% to ∼32%. The mechanistic basis for such differences in fatigue resistance or 'physiological resilience' are not resolved. However, resilience may be important in explaining superlative endurance performance and it has implications for the physiological evaluation of athletes and the design of interventions to enhance performance. This article presents new information concerning the dynamic plasticity of the three 'traditional' physiological variables and argues that physiological resilience should be considered as an additional component, or fourth dimension, in models of endurance exercise performance.

Keywords:  durability; exercise physiology; fatigue resistance; muscle fatigue; muscle metabolism; performance; respiratory physiology

DOI:  https://doi.org/10.1113/JP284205