bims-kimdis 2023-06-18 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–06–18
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Modulation of the autophagy-lysosomal pathway and endoplasmic reticulum stress by ketone bodies in experimental models of stroke.
Nicotinamide riboside functions during development while beta-hydroxybutyrate functions during adulthood to extend C. elegans lifespan.
Is there a role for ketones as alternative fuel in critical illness?
The Effects of a Very-Low-Calorie Ketogenic Diet on the Intestinal Barrier Integrity and Function in Patients with Obesity: A Pilot Study.
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.
A Case of Severe Metabolic Acidosis in the Setting of a Strict Ketogenic Diet.
Ketogenic Diet in Neonates with Drug-Resistant Epilepsy: Efficacy and Side Effects-A Single Center's Initial Experience.
Effects of ketone supplements on blood β-hydroxybutyrate, glucose and insulin: A systematic review and three-level meta-analysis.
Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]β-hydroxybutyrate ([11C]OHB) PET in healthy humans.
Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3-Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects.
Mitochondria: at the crossroads between mechanobiology and cell metabolism.
Exercise-induced regulation of adipose tissue.
Multi-tissue responses to exercise: A MoTrPAC feasibility study.
Low energy availability reduces myofibrillar and sarcoplasmic muscle protein synthesis in trained females.
β-Hydroxy-β-methyl Butyrate Regulates the Lipid Metabolism, Mitochondrial Function, and Fat Browning of Adipocytes.
PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
Mitochondrial quality control in cardiac fibrosis: Epigenetic mechanisms and therapeutic strategies.
Mitochondrial control of innate immune responses.
Comparison between the Astaxanthin Release Profile of Mesoporous Bioactive Glass Nanoparticles (MBGNs) and Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/MBGN Composite Microspheres.
Strength athletes and mitochondria: It's about 'time'.
Moderate exercise induces trained immunity in macrophages.
Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations.
Satellite cell contribution to disease pathology in Duchenne muscular dystrophy.
Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.

J Neurochem. 2023 Jun 16.

Modulation of the autophagy-lysosomal pathway and endoplasmic reticulum stress by ketone bodies in experimental models of stroke.

Teresa Montiel, Juan Carlos Gómora-García, Cristian Gerónimo-Olvera, Yessica Heras-Romero, Berenice N Bernal-Vicente, Xochitl Pérez-Martínez, Luis B Tovar-Y-Romo, Lourdes Massieu.

  Ischemic stroke is a leading cause of disability worldwide. There is no simple treatment to alleviate ischemic brain injury, as thrombolytic therapy is applicable within a narrow time window. During the last years, the ketogenic diet (KD) and the exogenous administration of the ketone body β-hydroxybutyrate (BHB) have been proposed as therapeutic tools for acute neurological disorders and both can reduce ischemic brain injury. However, the mechanisms involved are not completely clear. We have previously shown that the D enantiomer of BHB stimulates the autophagic flux in cultured neurons exposed to glucose deprivation (GD) and in the brain of hypoglycemic rats. Here, we have investigated the effect of the systemic administration of D-BHB, followed by its continuous infusion after middle cerebral artery occlusion (MCAO), on the autophagy-lysosomal pathway and the activation of the unfolded protein response (UPR). Results show for the first time that the protective effect of BHB against MCAO injury is enantiomer selective as only D-BHB, the physiologic enantiomer of BHB, significantly reduced brain injury. D-BHB treatment prevented the cleavage of the lysosomal membrane protein LAMP2 and stimulated the autophagic flux in the ischemic core and the penumbra. In addition, D-BHB notably reduced the activation of the PERK/eIF2α/ATF4 pathway of the UPR and inhibited IRE1α phosphorylation. L-BHB showed no significant effect relative to ischemic animals. In cortical cultures under GD, D-BHB prevented LAMP2 cleavage and decreased lysosomal number. It also abated the activation of the PERK/eIF2α/ATF4 pathway, partially sustained protein synthesis, and reduced pIRE1α. In contrast, L-BHB showed no significant effects. Results suggest that protection elicited by D-BHB treatment post-ischemia prevents lysosomal rupture allowing functional autophagy, preventing the loss of proteostasis and UPR activation.

Keywords:  Beta-hydroxybutyrate; Endoplasmic Reticulum stress; Glucose deprivation; Neuronal death; Proteostasis; Unfolded Protein Response

DOI:  https://doi.org/10.1111/jnc.15852
MicroPubl Biol. 2023 ;2023

Nicotinamide riboside functions during development while beta-hydroxybutyrate functions during adulthood to extend C. elegans lifespan.

J Dylan Peters, McKenzie P Peters, Patrick C Bradshaw.

Nicotinamide riboside (NR), a form of vitamin B3 and a nicotinamide adenine dinucleotide (NAD + ) precursor, has been shown to activate the mitochondrial unfolded protein response (UPR mt ) and extend the lifespan when supplemented to C. elegans. The ketone body and histone deacetylase (HDAC) inhibitor beta-hydroxybutyrate (BHB) has also been shown to extend C. elegans lifespan. Experiments were performed that showed that NR extended lifespan by acting almost exclusively during larval development, while BHB extended lifespan by acting during adulthood, and the combination of NR during development and BHB during adulthood unexpectedly decreased lifespan. This suggests that hormesis is involved in the lifespan-altering effects of BHB and NR and that they are inducing parallel longevity pathways that converge on a common downstream target.

DOI: https://doi.org/10.17912/micropub.biology.000841
Curr Opin Crit Care. 2023 Jun 01.

Is there a role for ketones as alternative fuel in critical illness?

Naomi Watson, Thomas J McClelland, Zudin Puthucheary.

PURPOSE OF REVIEW: The evidence base advocating ketones as an alternative substrate for critically ill patients is expanding. We discuss the rationale for investigating alternatives to the traditional metabolic substrates (glucose, fatty acids and amino acids), consider evidence relating to ketone-based nutrition in a variety of contexts, and suggest the necessary future steps.
RECENT FINDINGS: Hypoxia and inflammation inhibit pyruvate dehydrogenase, diverting glucose to lactate production. Skeletal muscle beta-oxidation activity falls, decreasing acetyl-CoA generation from fatty acids and subsequent ATP generation reduction.The benefits of induced ketosis are well established in epilepsy, whilst the evidence base for ketogenic diet therapy in other neurological pathology, such as traumatic brain injury and neurodegenerative diseases, is expanding. Evidence of upregulation of ketone metabolism in the hypertrophied and failing heart suggests that ketones may be utilized as an alternative fuel source to sustain myocardial function. Ketogenic diets stabilize immune cell homeostasis, promote cell survival following bacterial infection and inhibit the NLRP3 inflammasome, preventing the release of pro-inflammatory cytokines - interleukin (IL)-1β and IL-18.
SUMMARY: Whilst ketones provide an attractive nutritional option, further research is required to determine whether the proposed benefits are translatable to critically unwell patients.

DOI: https://doi.org/10.1097/MCC.0000000000001061
Nutrients. 2023 May 30. pii: 2561. [Epub ahead of print]15(11):

The Effects of a Very-Low-Calorie Ketogenic Diet on the Intestinal Barrier Integrity and Function in Patients with Obesity: A Pilot Study.

Michele Linsalata, Francesco Russo, Giuseppe Riezzo, Benedetta D'Attoma, Laura Prospero, Antonella Orlando, Antonia Ignazzi, Martina Di Chito, Annamaria Sila, Sara De Nucci, Roberta Rinaldi, Gianluigi Giannelli, Giovanni De Pergola.

  The very-low-calorie ketogenic diet (VLCKD) is effective and safe for obese individuals, but limited information exists on its impact on the intestinal barrier. This study analyzed the effects of 8 weeks of VLCKD on 24 obese patients (11M/13F). Carbohydrate intake was fixed at 20-50 g/day, while protein and lipid intake varied from 1-1.4 g/kg of ideal body weight and 15-30 g per day, respectively. Daily calorie intake was below 800 kcal. The lactulose-mannitol absorption test assessed small intestinal permeability. Multiple markers, such as serum and fecal zonulin, fatty acid-binding protein, diamine oxidase concentrations, urinary dysbiosis markers (indican and skatole), and circulating lipopolysaccharide levels, were analyzed. Inflammation markers (serum interleukin 6, 8, 10, and tumor necrosis factor-α concentrations) were also evaluated. The results showed significant reductions in weight, BMI, and waist circumference post-diet. However, the lactulose-mannitol ratio increased by 76.5%, and a significant increase in dysbiosis markers at the end of the diet occurred. This trend was particularly evident in a subgroup of patients. Despite initial benefits, the VLCKD might negatively affect the intestinal barrier function in obese patients, potentially worsening their compromised intestinal balance.

Keywords:  dysbiosis; inflammation; intestinal barrier; intestinal permeability; ketogenic diet; obesity

DOI:  https://doi.org/10.3390/nu15112561
Cell Metab. 2023 Jun 07. pii: S1550-4131(23)00185-7. [Epub ahead of print]

Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia.

Miriam Ferrer, Nicholas Mourikis, Emma E Davidson, Sam O Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Qing Gao, Thomas R Flint, Lisa Young, Claire M Connell, Michael J Lukey, Marcus D Goncalves, Eileen P White, Ashok R Venkitaraman, Tobias Janowitz.

  Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.

Keywords:  GDF-15; IL-6; NADPH; cachexia; cancer; corticosterone; ferroptosis; ketogenic diet; lipid peroxidation; steroid

DOI:  https://doi.org/10.1016/j.cmet.2023.05.008
Cureus. 2023 May;15(5): e38741

A Case of Severe Metabolic Acidosis in the Setting of a Strict Ketogenic Diet.

Kerrie E Ward, Jay Ramsay, Bao Joseph Vu.

  Patients with metabolic acidosis often present with obscure, multifactorial etiologies, making efficient diagnosis and treatment key to preventing poor clinical outcomes. This case report describes a patient with severe metabolic acidosis in which the underlying cause was not immediately apparent. After a thorough work-up and history taking, the patient's strict ketogenic diet was identified as the most likely source of his illness. Over multiple days, the patient improved as he resumed a normal diet and was treated for refeeding syndrome. This case highlights the importance of taking a comprehensive social and diet history when assessing a patient with metabolic acidosis. It also highlights the need for physicians to understand and be ready to counsel on the possible effects of fad diets, such as the ketogenic diet.

Keywords:  electrolyte abnormalities; ketogenic diet; metabolic acidosis; refeeding syndrome; starvation ketoacidosis

DOI:  https://doi.org/10.7759/cureus.38741
Neuropediatrics. 2023 Jun 15.

Ketogenic Diet in Neonates with Drug-Resistant Epilepsy: Efficacy and Side Effects-A Single Center's Initial Experience.

Raffaele Falsaperla, Vincenzo Sortino, Ausilia Desiree Collotta, Grete Francesca Privitera, Antonio Palmeri, Laura Mauceri, Martino Ruggieri.

BACKGROUND: For patients with pharmacoresistant epilepsy, a therapeutic option is ketogenic diet. Currently, data on young infants are scarce, particularly during hospitalization in the neonatal intensive care unit (NICU).
OBJECTIVE: The aim of the present study was to evaluate the short-term (3-month) efficacy and side effects of ketogenic diet in infants with "drugs-resistant" epilepsy treated during NICU stay.
METHODS: This retrospective study included infants aged under 2 months started on ketogenic diet during NICU hospitalization to treat drug-resistant epilepsy from April 2018 to November 2022.
RESULTS: Thirteen term-born infants were included, three (23.1%) of whom were excluded because they did not respond to the ketogenic diet. Finally, we included 10 infants. Six (60%) patients took three antiepileptics before starting the ketogenic diet, while four (40%) took more drugs. Diet had a good response in four (40%) patients. In four patients, the ketogenic diet was suspended because of the onset of serious side effects. The emetic levels of sodium, potassium, and chlorine, pH, and onset of diarrhea, constipation, and gastroesophageal reflux showed significant differences. Ketonuria was higher and blood pH lower in the group that took more than three drugs than in the group taking fewer than three drugs.
CONCLUSION: The ketogenic diet is efficacious and safe in infants, but the early and aggressive management of adverse reactions is important to improve the safety and effectiveness of the ketogenic treatment.

DOI: https://doi.org/10.1055/s-0043-1769505
Complement Ther Clin Pract. 2023 Jun 10. pii: S1744-3881(23)00055-5. [Epub ahead of print]52 101774

Effects of ketone supplements on blood β-hydroxybutyrate, glucose and insulin: A systematic review and three-level meta-analysis.

Qian Yu, Kaja Falkenhain, Jonathan P Little, Ka Kit Wong, Jinlei Nie, Qingde Shi, Zhaowei Kong.

   BACKGROUND: Effects of ketone supplements as well as relevant dose-response relationships and time effects on blood β-hydroxybutyrate (BHB), glucose and insulin are controversial.
OBJECTIVE: This study aimed to summarize the existing evidence and synthesize the results, and demonstrate underlying dose-response relationships as well as sustained time effects.
METHODS: Medline, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant randomized crossover/parallel studies published until 25th November 2022. Three-level meta-analysis compared the acute effects of exogenous ketone supplementation and placebo in regulating blood parameters, with Hedge's g used as measure of effect size. Effects of potential moderators were explored through multilevel regression models. Dose-response and time-effect models were established via fractional polynomial regression.
RESULTS: The meta-analysis with 327 data points from 30 studies (408 participants) indicated that exogenous ketones led to a significant increase in blood BHB (Hedge's g = 1.4994, 95% CI [1.2648, 1.7340]), reduction in glucose (Hedge's g = -0.3796, 95% CI [-0.4550, -0.3041]), and elevation in insulin of non-athlete healthy population (Hedge's g = 0.1214, 95%CI [0.0582, 0.3011]), as well as insignificant change in insulin of obesity and prediabetes. Nonlinear dose-response relationship between ketone dosage and blood parameter change was observed in some time intervals for BHB (30-60 min; >120 min) and insulin (30-60 min; 90-120 min), with linear relationship observed for glucose (>120 min). Nonlinear associations between time and blood parameter change were found in BHB (>550 mg/kg) and glucose (450-550 mg/kg), with linear relationship observed in BHB (≤250 mg/kg) and insulin (350-550 mg/kg).
CONCLUSION: Dose-response relationships and sustained time effects were observed in BHB, glucose and insulin following ketone supplementation. Glucose-lowering effect without increasing insulin load among population of obesity and prediabetes was of remarkable clinical implication.
REGISTRY AND REGISTRY NUMBER: PROSPERO (CRD42022360620).

Keywords:  Dose response; Glucose; Insulin; Ketone; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.ctcp.2023.101774
Sci Immunol. 2023 Jun 23. 8(84): eade7652

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.

Sung Hoon Baik, V Krishnan Ramanujan, Courtney Becker, Sarah Fett, David M Underhill, Andrea J Wolf.

NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.

DOI: https://doi.org/10.1126/sciimmunol.ade7652
EJNMMI Radiopharm Chem. 2023 Jun 14. 8(1): 12

Intravenous and oral whole body ketone dosimetry, biodistribution, metabolite correction and kinetics studied by (R)-[1-11C]β-hydroxybutyrate ([11C]OHB) PET in healthy humans.

Thien Vinh Luong, Erik Nguyen Nielsen, Lise Falborg, Mette Louise Gram Kjærulff, Lars Poulsen Tolbod, Esben Søndergaard, Niels Møller, Ole Lajord Munk, Lars Christian Gormsen.

   BACKGROUND: Ketones are increasingly recognized as an important and possibly oxygen sparing source of energy in vital organs such as the heart, the brain and the kidneys. Drug treatments, dietary regimens and oral ketone drinks designed to deliver ketones for organ and tissue energy production have therefore gained popularity. However, whether ingested ketones are taken up by various extra-cerebral tissues and to what extent is still largely unexplored. It was therefore the aim of this study to use positron emission tomography (PET) to explore the whole body dosimetry, biodistribution and kinetics of the ketone tracer (R)-[1-11C]β-hydroxybutyrate ([11C]OHB). Six healthy subjects (3 women and 3 men) underwent dynamic PET studies after both intravenous (90 min) and oral (120 min) administration of [11C]OHB. Dosimetry estimates of [11C]OHB was calculated using OLINDA/EXM software, biodistribution was assessed visually and [11C]OHB tissue kinetics were obtained using an arterial input function and tissue time-activity curves.
RESULTS: Radiation dosimetry yielded effective doses of 3.28 [Formula: see text]Sv/MBq (intravenous administration) and 12.51 [Formula: see text]Sv/MBq (oral administration). Intravenous administration of [11C]OHB resulted in avid radiotracer uptake in the heart, liver, and kidneys, whereas lesser uptake was observed in the salivary glands, pancreas, skeletal muscle and red marrow. Only minimal uptake was noted in the brain. Oral ingestion of the tracer resulted in rapid radiotracer appearance in the blood and radiotracer uptake in the heart, liver and kidneys. In general, [11C]OHB tissue kinetics after intravenous administration were best described by a reversible 2-tissue compartmental model.
CONCLUSION: The PET radiotracer [11C]OHB shows promising potential in providing imaging data on ketone uptake in various physiologically relevant tissues. As a result, it may serve as a safe and non-invasive imaging tool for exploring ketone metabolism in organs and tissues of both patients and healthy individuals. Trial registration Clinical trials, NCT0523812, Registered February 10th 2022, https://clinicaltrials.gov/ct2/show/NCT05232812?cond=NCT05232812&draw=2&rank=1 .

Keywords:  Biodistribution; Dosimetry; Ketone metabolism; Kinetics; PET/CT

DOI:  https://doi.org/10.1186/s41181-023-00198-z
J Am Heart Assoc. 2023 Jun 10. e029849

Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3-Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects.

Nigopan Gopalasingam, Kristian Hylleberg Christensen, Kristoffer Berg Hansen, Roni Nielsen, Mogens Johannsen, Lars Christian Gormsen, Ebbe Boedtkjer, Rikke Nørregaard, Niels Møller, Henrik Wiggers.

  Background The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3-OHB activates the hydroxycarboxylic acid receptor 2 (HCA2), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3-OHB involved HCA2 activation and if the potent HCA2-stimulator niacin may increase CO. Methods and Results Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA2 downstream cyclooxygenase enzyme, followed by 3-OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3-OHB increased CO (2.3 L/min, P<0.01), stroke volume (19 mL, P<0.01), heart rate (10 bpm, P<0.01), and mixed venous saturation (5%, P<0.01) with preceding aspirin. 3-OHB did not change prostaglandin levels, neither in the ketone/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3-OHB-induced changes in CO (P=0.43). 3-OHB decreased free fatty acids by 58% (P=0.01). Niacin increased prostaglandin D2 levels by 330% (P<0.02) and reduced free fatty acids by 75% (P<0.01) but did not affect CO. Conclusions The acute increase in CO during 3-OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA2 receptor-mediated effects were not involved in the hemodynamic response to 3-OHB. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04703361.

Keywords:  HCA2 receptor; heart failure; hemodynamics; ketone body; metabolic

DOI:  https://doi.org/10.1161/JAHA.123.029849
Biol Cell. 2023 Jun 16.

Mitochondria: at the crossroads between mechanobiology and cell metabolism.

Émilie Su, Catherine Villard, Jean-Baptiste Manneville.

  Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer. This article is protected by copyright. All rights reserved.

Keywords:  Mitochondrial morphodynamics; cancer; cytoskeleton; glycolysis; mechanotransduction; membrane tension; oxidative phosphorylation

DOI:  https://doi.org/10.1111/boc.202300010
Curr Opin Genet Dev. 2023 Jun 07. pii: S0959-437X(23)00038-2. [Epub ahead of print]81 102058

Exercise-induced regulation of adipose tissue.

Andrew M Stroh, Kristin I Stanford.

Exercise induces various beneficial whole-body adaptations and can delay the onset of obesity, type 2 diabetes, and cardiovascular disease. While many of the beneficial effects of exercise on skeletal muscle and the cardiovascular system have been well established, recent studies have highlighted the role of exercise-induced improvements to adipose tissue that affect metabolic and whole-body health. Studies investigating exercise-induced adaptations of white adipose tissue (WAT) and brown adipose tissue (BAT) demonstrate modifications to glucose uptake, mitochondrial activity, and endocrine profile, and a beiging of WAT in rodents. This review discusses recent studies of the exercise-induced adaptations to WAT and BAT and their implications.

DOI: https://doi.org/10.1016/j.gde.2023.102058
J Appl Physiol (1985). 2023 Jun 15.

Multi-tissue responses to exercise: A MoTrPAC feasibility study.

Toby L Chambers, Andrew M Stroh, Clarisa Chavez, Anna R Brandt, Alex Claiborne, William A Fountain, Kevin J Gries, Andrew M Jones, Dillon J Kuszmaul, Gary E Lee, Bridget E Lester, Colleen E Lynch, Kiril Minchev, Cristhian F Montenegro, Masatoshi Naruse, Ulrika Raue, Todd A Trappe, Scott Trappe.

  We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25±2yr, 12M, 8W) completed an endurance exercise bout (n=8, 40 min cycling at 70% VO2max), a resistance exercise bout (n=6, ~45 min, 3 sets of ~10 repetition maximum, 8 exercises), or a resting control period (n=6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2h, 3.5h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (peri-umbilical) biopsies were taken before and ~4h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) were reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, while skeletal muscle was transcriptionally more responsive than adipose 4h post-exercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.

Keywords:  MoTrPAC; adipose; gene expression; metabolism; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00210.2023
J Physiol. 2023 Jun 16.

Low energy availability reduces myofibrillar and sarcoplasmic muscle protein synthesis in trained females.

Mikkel Oxfeldt, Stuart M Phillips, Ole Emil Andersen, Frank Ted Johansen, Maj Bangshaab, Jeyanthini Risikesan, James McKendry, Anna Katarina Melin, Mette Hansen.

  Low energy availability (LEA) describes a state where energy intake is insufficient to cover the energy costs of both exercise energy expenditure and basal physiological body functions. LEA has been associated with various physiological consequences, such as reproductive dysfunction. However, the effect of LEA on skeletal muscle protein synthesis in females performing exercise training is still poorly understood. We conducted a randomized controlled trial investigating the impact of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in trained females. Thirty eumenorrheic females were matched based on training history and randomized to undergo 10 days of LEA (25 kcal · kg Fat-Free Mass (FFM)-1 · day-1 ) or optimal energy availability (OEA, 50 kcal · kg FFM-1 · day-1 ). Before the intervention, both groups underwent a five-day 'run-in' period with OEA. All foods were provided throughout the experimental period with a protein content of 2.2 g · kg lean mass-1 · day-1 . A standardized, supervised combined resistance and cardiovascular exercise training program was performed over the experimental period. Daily integrated muscle protein synthesis was measured by deuterium oxide (D2 O) consumption along with changes in body composition, resting metabolic rate, blood biomarkers, and 24h nitrogen balance. We found that LEA reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared to OEA. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations, and resting metabolic rate following LEA. These results highlight that LEA may negatively affect skeletal muscle adaptations in females performing exercise training. KEY POINTS: Low energy availability with potential health and performance impairments is widespread among female athletes. We investigated the impact of 10 days of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in young, trained females. We show that LEA impairs myofibrillar and sarcoplasmic muscle protein synthesis in trained females performing exercise training. These findings suggest that LEA may have negative consequences for skeletal muscle adaptations and highlight the importance of ensuring adequate energy availability in female athletes. Abstract Figure Legend Ten days of low energy availability in trained females performing supervised exercise training resulted in reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared to optimal energy availability. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations, and resting metabolic rate following low energy availability. This article is protected by copyright. All rights reserved.

Keywords:  Energy restriction; Female athlete; Menstrual dysfunctions; RED-S

DOI:  https://doi.org/10.1113/JP284967
Nutrients. 2023 May 30. pii: 2550. [Epub ahead of print]15(11):

β-Hydroxy-β-methyl Butyrate Regulates the Lipid Metabolism, Mitochondrial Function, and Fat Browning of Adipocytes.

Geyan Duan, Changbing Zheng, Jiayi Yu, Peiwen Zhang, Mengliao Wan, Jie Zheng, Yehui Duan.

  A growing number of in vivo studies demonstrated that β-hydroxy-β-methyl butyrate (HMB) can serve as a lipid-lowering nutrient. Despite this interesting observation, the use of adipocytes as a model for research is yet to be explored. To ascertain the effects of HMB on the lipid metabolism of adipocytes and elucidate the underlying mechanisms, the 3T3-L1 cell line was employed. Firstly, serial doses of HMB were added to 3T3-L1 preadipocytes to evaluate the effects of HMB on cell proliferation. HMB (50 µM) significantly promoted the proliferation of preadipocytes. Next, we investigated whether HMB could attenuate fat accumulation in adipocytes. The results show that HMB treatment (50 µM) reduced the triglyceride (TG) content. Furthermore, HMB was found to inhibit lipid accumulation by suppressing the expression of lipogenic proteins (C/EBPα and PPARγ) and increasing the expression of lipolysis-related proteins (p-AMPK, p-Sirt1, HSL, and UCP3). We also determined the concentrations of several lipid metabolism-related enzymes and fatty acid composition in adipocytes. The HMB-treated cells showed reduced G6PD, LPL, and ATGL concentrations. Moreover, HMB improved the fatty acid composition in adipocytes, manifested by increases in the contents of n6 and n3 PUFAs. The enhancement of the mitochondrial respiratory function of 3T3-L1 adipocytes was confirmed via Seahorse metabolic assay, which showed that HMB treatment elevated basal mitochondrial respiration, ATP production, H+ leak, maximal respiration, and non-mitochondrial respiration. In addition, HMB enhanced fat browning of adipocytes, and this effect might be associated with the activation of the PRDM16/PGC-1α/UCP1 pathway. Taken together, HMB-induced changes in the lipid metabolism and mitochondrial function may contribute to preventing fat deposition and improving insulin sensitivity.

Keywords:  fat browning; insulin resistance; lipid metabolism; mitochondrial biogenesis; β-hydroxy-β-methyl butyrate

DOI:  https://doi.org/10.3390/nu15112550
EMBO J. 2023 Jun 12. e113908

PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.

Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.

  Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.

Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)

DOI:  https://doi.org/10.15252/embj.2023113908
Metabolism. 2023 Jun 09. pii: S0026-0495(23)00230-5. [Epub ahead of print]145 155626

Mitochondrial quality control in cardiac fibrosis: Epigenetic mechanisms and therapeutic strategies.

Li-Chan Lin, Bin Tu, Kai Song, Zhi-Yan Liu, He Sun, Yang Zhou, Ji-Ming Sha, Jing-Jing Yang, Ye Zhang, Jian-Yuan Zhao, Hui Tao.

  Cardiac fibrosis (CF) is considered an ultimate common pathway of a wide variety of heart diseases in response to diverse pathological and pathophysiological stimuli. Mitochondria are characterized as isolated organelles with a double-membrane structure, and they primarily contribute to and maintain highly dynamic energy and metabolic networks whose distribution and structure exert potent support for cellular properties and performance. Because the myocardium is a highly oxidative tissue with high energy demands to continuously pump blood, mitochondria are the most abundant organelles within mature cardiomyocytes, accounting for up to one-third of the total cell volume, and play an essential role in maintaining optimal performance of the heart. Mitochondrial quality control (MQC), including mitochondrial fusion, fission, mitophagy, mitochondrial biogenesis, and mitochondrial metabolism and biosynthesis, is crucial machinery that modulates cardiac cells and heart function by maintaining and regulating the morphological structure, function and lifespan of mitochondria. Certain investigations have focused on mitochondrial dynamics, including manipulating and maintaining the dynamic balance of energy demand and nutrient supply, and the resultant findings suggest that changes in mitochondrial morphology and function may contribute to bioenergetic adaptation during cardiac fibrosis and pathological remodeling. In this review, we discuss the function of epigenetic regulation and molecular mechanisms of MQC in the pathogenesis of CF and provide evidence for targeting MQC for CF. Finally, we discuss how these findings can be applied to improve the treatment and prevention of CF.

Keywords:  Cardiac fibrosis; Epigenetics; Extracellular matrix; Mitochondrial quality control

DOI:  https://doi.org/10.1016/j.metabol.2023.155626
Front Immunol. 2023 ;14 1166214

Mitochondrial control of innate immune responses.

Shasha Chen, Zhiyong Liao, Pinglong Xu.

  Mitochondria are versatile organelles and essential components of numerous biological processes such as energy metabolism, signal transduction, and cell fate determination. In recent years, their critical roles in innate immunity have come to the forefront, highlighting impacts on pathogenic defense, tissue homeostasis, and degenerative diseases. This review offers an in-depth and comprehensive examination of the multifaceted mechanisms underlying the interactions between mitochondria and innate immune responses. We will delve into the roles of healthy mitochondria as platforms for signalosome assembly, the release of mitochondrial components as signaling messengers, and the regulation of signaling via mitophagy, particularly to cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling and inflammasomes. Furthermore, the review will explore the impacts of mitochondrial proteins and metabolites on modulating innate immune responses, the polarization of innate immune cells, and their implications on infectious and inflammatory diseases.

Keywords:  MAVS; cGAS-STING; inflammasome; innate immunity; mitochondria; mitochondrial metabolism; mitophagy; mtDNA

DOI:  https://doi.org/10.3389/fimmu.2023.1166214
Polymers (Basel). 2023 May 24. pii: 2432. [Epub ahead of print]15(11):

Comparison between the Astaxanthin Release Profile of Mesoporous Bioactive Glass Nanoparticles (MBGNs) and Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV)/MBGN Composite Microspheres.

Arturo E Aguilar-Rabiela, Shahin Homaeigohar, Eduin I González-Castillo, Mirna L Sánchez, Aldo R Boccaccini.

  In recent years, composite biomaterials have attracted attention for drug delivery applications due to the possibility of combining desired properties of their components. However, some functional characteristics, such as their drug release efficiency and likely side effects, are still unexplored. In this regard, controlled tuning of the drug release kinetic via the precise design of a composite particle system is still of high importance for many biomedical applications. This objective can be properly fulfilled through the combination of different biomaterials with unequal release rates, such as mesoporous bioactive glass nanoparticles (MBGN) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microspheres. In this work, MBGNs and PHBV-MBGN microspheres, both loaded with Astaxanthin (ASX), were synthesised and compared in terms of ASX release kinetic, ASX entrapment efficiency, and cell viability. Moreover, the correlation of the release kinetic to phytotherapeutic efficiency and side effects was established. Interestingly, there were significant differences between the ASX release kinetic of the developed systems, and cell viability differed accordingly after 72 h. Both particle carriers effectively delivered ASX, though the composite microspheres exhibited a more prolonged release profile with sustained cytocompatibility. The release behaviour could be fine-tuned by adjusting the MBGN content in the composite particles. Comparatively, the composite particles induced a different release effect, implying their potential for sustained drug delivery applications.

Keywords:  Astaxanthin; composite microspheres; controlled release; sustained release

DOI:  https://doi.org/10.3390/polym15112432
J Physiol. 2023 Jun 12.

Strength athletes and mitochondria: It's about 'time'.

Madison C Garibotti, Christopher G R Perry.



Keywords:  exercise; mitochondria; muscle

DOI:  https://doi.org/10.1113/JP284856
Am J Physiol Cell Physiol. 2023 Jun 12.

Moderate exercise induces trained immunity in macrophages.

Mayoorey Murugathasan, Ardavan Jafari, Amandeep Amandeep, Syed A Hassan, Matthew Chihata, Ali A Abdul-Sater.

  Despite its importance in protecting the host from infections and injury, excessive inflammation may lead to serious human diseases including autoimmune disorders, cardiovascular diseases, diabetes, and cancer. Exercise is a known immunomodulator; however, whether exercise causes long term changes in inflammatory responses and how these changes occur are lacking. Here, we show that chronic moderate intensity training of mice leads to persistent metabolic rewiring and changes to chromatin accessibility in bone marrow derived macrophages (BMDMs), which, in turn, tempers their inflammatory responses. We show that BMDMs from exercised mice exhibited a decrease in lipopolysaccharide (LPS) induced NF-kB activation and pro-inflammatory gene expression along with an increase in M2-like associated genes when compared to BMDMs from sedentary mice. This was associated with improved mitochondrial quality and increased reliance on oxidative phosphorylation accompanied with reduced mitochondrial ROS production. Mechanistically, ATAC-seq analysis showed changes in chromatin accessibility of genes associated with inflammatory and metabolic pathways. Overall, our data suggest that chronic moderate exercise can influence the inflammatory responses of macrophages by reprogramming their metabolic and epigenetic landscape.

Keywords:  Exercise; Inflammation; Macrophages; Mitochondria; epigenetic

DOI:  https://doi.org/10.1152/ajpcell.00130.2023
J Neurochem. 2023 Jun 13.

Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations.

Oliver Kann.

  Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30-70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation-inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5'-triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.

Keywords:  brain slice technique; concentration gradient; immunometabolism; neuronal activation; nitric oxide; postsynaptic current

DOI:  https://doi.org/10.1111/jnc.15867
Front Physiol. 2023 ;14 1180980

Satellite cell contribution to disease pathology in Duchenne muscular dystrophy.

Kasun Kodippili, Michael A Rudnicki.

  Progressive muscle weakness and degeneration characterize Duchenne muscular dystrophy (DMD), a lethal, x-linked neuromuscular disorder that affects 1 in 5,000 boys. Loss of dystrophin protein leads to recurrent muscle degeneration, progressive fibrosis, chronic inflammation, and dysfunction of skeletal muscle resident stem cells, called satellite cells. Unfortunately, there is currently no cure for DMD. In this mini review, we discuss how satellite cells in dystrophic muscle are functionally impaired, and how this contributes to the DMD pathology, and the tremendous potential of restoring endogenous satellite cell function as a viable treatment strategy to treat this debilitating and fatal disease.

Keywords:  Duchenne muscular dystrophy; asymmetric cell division; dystrophin; muscle regeneration; myogenesis; satellite cells; skeletal muscle stem cells; symmetric cell division

DOI:  https://doi.org/10.3389/fphys.2023.1180980
Free Radic Biol Med. 2023 Jun 07. pii: S0891-5849(23)00430-6. [Epub ahead of print]

Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.

Patricia Sánchez-Pérez, Ana Mata, May-Kristin Torp, Elia López-Bernardo, Christina M Heiestad, Jan Magnus Aronsen, Antonio Molina-Iracheta, Luis J Jiménez-Borreguero, Pablo García-Roves, Ana S H Costa, Christian Frezza, Michael P Murphy, Kåre-Olav Stenslokken, Susana Cadenas.

  Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.

Keywords:  Energy metabolism; Ischemia-reperfusion injury; Mitochondrial respiration; Mitochondrial structure; Oxidative stress; UCP3 (uncoupling protein 3)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.014