bims-kimdis 2024-04-14 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒04‒14
24 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice.
A maternal ketogenic diet alters oviduct fluid nutrients and embryo histone acetylation in mice.
Hepatic ketone body regulation of renal gluconeogenesis.
Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis.
Ketone Monoester Followed by Carbohydrate Ingestion after Glycogen-Lowering Exercise Does Not Improve Subsequent Endurance Cycle Time Trial Performance.
High Fat Diet and Polycystic Ovary Syndrome (PCOS) in Adolescence: An Overview of Nutritional Strategies.
Impact of Ketogenic and Low-Glycemic Diets on Inflammatory Skin Conditions.
Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy.
Point-of-care β-hydroxybutyrate measurement predicts adequate glucose metabolism suppression in cardiac FDG-PET/CT.
Neuroprotective effects of lactate and ketone bodies in acute brain injury.
Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.
Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1).
Study Examines Intermittent Fasting and Cardiovascular Mortality.
Skeletal muscle mitochondrial correlates of critical power and W' in healthy active individuals.
Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy.
Mechanisms of body fat distribution and gluteal-femoral fat protection against metabolic disorders.
Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.
Association of Obesity with Telomere Length in Human Sperm.
Substituting carbohydrate at lunch for added protein increases fat oxidation during subsequent exercise in healthy males.
Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.
Inhibition of Carbohydrate Metabolism Potentiated by the Therapeutic Effects of Oxidative Phosphorylation Inhibitors in Colon Cancer Cells.
The effect of oral butyrate on colonic short-chain fatty acid transporters and receptors depends on microbial status.
Curcumin regulates autophagy through SIRT3-SOD2-ROS signaling pathway to improve quadriceps femoris muscle atrophy in KOA rat model.
MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.

J Nutr Health Aging. 2024 Apr 05. pii: S1279-7707(24)00306-3. [Epub ahead of print]28(6): 100219

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice.

Carlos J Padilla, Hallie Harris, Jeff S Volek, Brian C Clark, W David Arnold.

  OBJECTIVE: Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice.DESIGN: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention.
SETTING: Preclinical laboratory study.
SAMPLE SIZE: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)].
MEASUREMENTS: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels.
STATISTICAL ANALYSIS: Primary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function.
RESULTS: Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871).
CONCLUSION: KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

Keywords:  Aging; Ketogenic diet; Motor function; Motor units number estimation

DOI:  https://doi.org/10.1016/j.jnha.2024.100219
Reproduction. 2024 Apr 01. pii: REP-24-0026. [Epub ahead of print]

A maternal ketogenic diet alters oviduct fluid nutrients and embryo histone acetylation in mice.

Emma G Whatley, Alexandra J Harvey, David K Gardner.

A ketogenic diet elevates blood β-hydroxybutyrate to concentrations that perturb the development, metabolism, histone acetylation (H3K27ac) and viability of preimplantation mouse embryos in vitro. However, whether a ketogenic diet alters β-hydroxybutyrate concentrations within female reproductive fluid is unknown. This study aimed to quantify glucose and β-hydroxybutyrate within mouse blood and oviduct fluid following standard diet and ketogenic diet consumption and to assess whether a maternal periconceptional ketogenic diet impacts in vivo embryo development and blastocyst H3K27ac. Female C57BL/6 x CBA mice were fed a standard or ketogenic diet (n=24 each) for 24-27 days. Glucose and β-hydroxybutyrate were quantified in blood via an electronic monitoring system, and in oviduct fluid via ultramicrofluorescence. The developmental grade of flushed blastocysts was recorded, and blastocyst cell number and H3K27ac was assessed via immunofluorescence. A maternal ketogenic diet elevated β-hydroxybutyrate in day 24 blood (P<0.001) and oviduct fluid (P<0.05) compared with a standard diet, whereas glucose was unchanged. A periconceptional ketogenic diet did not impact blastocyst cell number, however, significantly delayed blastocyst development (P<0.05) and reduced trophectoderm-specific H3K27ac (P<0.05) compared with standard diet-derived embryos. Maternal ketogenic diet consumption is therefore associated with reproductive tract nutrient changes and altered embryonic development and epigenetics in vivo. Future studies to assess whether periconceptional/gestational ketogenic diet consumption impacts human preimplantation, fetal, and long-term offspring development and health are warranted.

DOI: https://doi.org/10.1530/REP-24-0026
Mol Metab. 2024 Apr 09. pii: S2212-8778(24)00065-6. [Epub ahead of print] 101934

Hepatic ketone body regulation of renal gluconeogenesis.

Ryo Hatano, Eunyoung Lee, Hiromi Sato, Masahiro Kiuchi, Kiyoshi Hirahara, Yoshimi Nakagawa, Hitoshi Shimano, Toshinori Nakayama, Tomoaki Tanaka, Takashi Miki.

  OBJECTIVES: During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood β-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications.METHODS: Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα-/-) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of β-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells.
RESULTS: Renal gluconeogenic genes were transactivated concurrently with blood β-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα-/- mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα-/- mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα-/- mice. In vitro experiments and metabolome analysis in renal tubular cells showed that β-hydroxybutyrate directly promotes glucose and NH3 production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that β-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPβ.
CONCLUSIONS: Our findings demonstrate that β-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.

Keywords:  acid-base homeostasis; glucose metabolism; ketone bodies; renal gluconeogenesis

DOI:  https://doi.org/10.1016/j.molmet.2024.101934
Nutr Diabetes. 2024 Apr 12. 14(1): 18

Role of liver FGF21-KLB signaling in ketogenic diet-induced amelioration of hepatic steatosis.

Wanrong Guo, Huanyi Cao, Yunfeng Shen, Wuguo Li, Wei Wang, Lidan Cheng, Mengyin Cai, Fen Xu.

BACKGROUND: The effectiveness of ketogenic diet (KD) in ameliorating fatty liver has been established, although its mechanism is under investigation. Fibroblast growth factor 21 (FGF21) positively regulates obesity-associated metabolic disorders and is elevated by KD. FGF21 conventionally initiates its intracellular signaling via receptor β-klotho (KLB). However, the mechanistic role of FGF21-KLB signaling for KD-ameliorated fatty liver remains unknown. This study aimed to delineate the critical role of FGF21 signaling in the ameliorative effects of KD on hepatic steatosis.METHODS: Eight-week-old C57BL/6 J mice were fed a chow diet (CD), a high-fat diet (HFD), or a KD for 16 weeks. Adeno-associated virus-mediated liver-specific KLB knockdown mice and control mice were fed a KD for 16 weeks. Phenotypic assessments were conducted during and after the intervention. We investigated the mechanism underlying KD-alleviated hepatic steatosis using multi-omics and validated the expression of key genes.
RESULTS: KD improved hepatic steatosis by upregulating fatty acid oxidation and downregulating lipogenesis. Transcriptional analysis revealed that KD dramatically activated FGF21 pathway, including KLB and fibroblast growth factor receptor 1 (FGFR1). Impairing liver FGF21 signaling via KLB knockdown diminished the beneficial effects of KD on ameliorating fatty liver, insulin resistance, and regulating lipid metabolism.
CONCLUSION: KD demonstrates beneficial effects on diet-induced metabolic disorders, particularly on hepatic steatosis. Liver FGF21-KLB signaling plays a critical role in the KD-induced amelioration of hepatic steatosis.

DOI: https://doi.org/10.1038/s41387-024-00277-3
Nutrients. 2024 Mar 23. pii: 932. [Epub ahead of print]16(7):

Ketone Monoester Followed by Carbohydrate Ingestion after Glycogen-Lowering Exercise Does Not Improve Subsequent Endurance Cycle Time Trial Performance.

Manuel D Quinones, Kyle Weiman, Peter W R Lemon.

  Relative to carbohydrate (CHO) alone, exogenous ketones followed by CHO supplementation during recovery from glycogen-lowering exercise have been shown to increase muscle glycogen resynthesis. However, whether this strategy improves subsequent exercise performance is unknown. The objective of this study was to assess the efficacy of ketone monoester (KME) followed by CHO ingestion after glycogen-lowering exercise on subsequent 20 km (TT20km) and 5 km (TT5km) best-effort time trials. Nine recreationally active men (175.6 ± 5.3 cm, 72.9 ± 7.7 kg, 28 ± 5 y, 12.2 ± 3.2% body fat, VO2max = 56.2 ± 5.8 mL· kg BM-1·min-1; mean ± SD) completed a glycogen-lowering exercise session, followed by 4 h of recovery and subsequent TT20km and TT5km. During the first 2 h of recovery, participants ingested either KME (25 g) followed by CHO at a rate of 1.2 g·kg-1·h-1 (KME + CHO) or an iso-energetic placebo (dextrose) followed by CHO (PLAC + CHO). Blood metabolites during recovery and performance during the subsequent two-time trials were measured. In comparison to PLAC + CHO, KME + CHO displayed greater (p < 0.05) blood beta-hydroxybutyrate concentration during the first 2 h, lower (p < 0.05) blood glucose concentrations at 30 and 60 min, as well as greater (p < 0.05) blood insulin concentration 2 h following ingestion. However, no treatment differences (p > 0.05) in power output nor time to complete either time trial were observed vs. PLAC + CHO. These data indicate that the metabolic changes induced by KME + CHO ingestion following glycogen-lowering exercise are insufficient to enhance subsequent endurance time trial performance.

Keywords:  exercise recovery; exogenous ketones; glycogen repletion; insulin; ketosis

DOI:  https://doi.org/10.3390/nu16070932
Nutrients. 2024 Mar 24. pii: 938. [Epub ahead of print]16(7):

High Fat Diet and Polycystic Ovary Syndrome (PCOS) in Adolescence: An Overview of Nutritional Strategies.

Valeria Calcaterra, Vittoria Carlotta Magenes, Giulia Massini, Luisa De Sanctis, Valentina Fabiano, Gianvincenzo Zuccotti.

  Polycystic ovary syndrome (PCOS) is a multifaceted and heterogeneous disorder, linked with notable reproductive, metabolic, and psychological outcomes. During adolescence, key components of PCOS treatment involve weight loss achieved through lifestyle and dietary interventions, subsequently pursued by pharmacological or surgical therapies. Nutritional interventions represent the first-line therapeutic approach in adolescents affected by PCOS, but different kinds of dietary protocols exist, so it is necessary to clarify the effectiveness and benefits of the most well-known nutritional approaches. We provided a comprehensive review of the current literature concerning PCOS definition, pathophysiology, and treatment options, highlighting nutritional strategies, particularly those related to high-fat diets. The high-fat nutritional protocols proposed in the literature, such as the ketogenic diet (KD), appear to provide benefits to patients with PCOS in terms of weight loss and control of metabolic parameters. Among the different types of KD studies, very low-calorie ketogenic diets (VLCKD), can be considered an effective dietary intervention for the short-term treatment of patients with PCOS. It rapidly leads to weight loss alongside improvements in body composition and metabolic profile. Even though extremely advantageous, long-term adherence to the KD is a limiting factor. Indeed, this dietary regimen could become unsustainable due to the important restrictions required for ketosis development. Thus, a combination of high-fat diets with more nutrient-rich nutritional regimens, such as the Mediterranean diet, can amplify positive effects for individuals with PCOS.

Keywords:  adolescents; high-fat diet; ketogenic diet; nutritional strategies; polycystic ovary syndrome

DOI:  https://doi.org/10.3390/nu16070938
Cutis. 2024 Feb;113(2): 75-80

Impact of Ketogenic and Low-Glycemic Diets on Inflammatory Skin Conditions.

Katie Roster, Lillian Xie, Terry Nguyen, Shari R Lipner.

Diet plays an emerging role in dermatologic therapy. The ketogenic and low-glycemic diets have potential anti-inflammatory and metabolic effects, making them attractive for treating inflammatory skin conditions. We provide an overview of the current evidence on the effects of ketogenic and low-glycemic diets on inflammatory skin conditions including acne, psoriasis, seborrheic dermatitis (SD), atopic dermatitis (AD), and hidradenitis suppurativa (HS). We conclude that low-glycemic diets show promise for treating acne, while the evidence for ketogenic diets in treating other inflammatory skin conditions is limited. Randomized clinical trials are needed to explore the efficacy of these diets as stand-alone or adjunctive treatments for inflammatory skin conditions.

DOI: https://doi.org/10.12788/cutis.0942
Cancer Res. 2024 Apr 08.

Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy.

Sean Murphy, Sharif Rahmy, Dailin Gan, Guoqiang Liu, Yini Zhu, Maxim Manyak, Loan Duong, Jianping He, James H Schofield, Zachary T Schafer, Jun Li, Xuemin Lu, Xin Lu.

Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer (PCa) poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant PCa cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or dietary supplementation of the ketone body β-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed PCa tumor growth as monotherapy, and both BHB and adaptive immunity were required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for PCa.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2742
Clin Physiol Funct Imaging. 2024 Apr 08.

Point-of-care β-hydroxybutyrate measurement predicts adequate glucose metabolism suppression in cardiac FDG-PET/CT.

Suvi Hartikainen, Tuomo Tompuri, Tiina Laitinen, Tomi Laitinen.

  AIMS: The aims of our study were to evaluate whether point-of-care β-hydroxybutyrate (BHB) measurement can be used to identify patients with adequate cardiac glucose metabolism suppression for cardiac [18F]-fluoro-2-deoxy- d-glucose-positron emission tomography with computerized tomography (FDG-PET/CT) and to develop a pretest probability calculator of myocardial suppression using other metabolic factors attainable before imaging.METHODS AND RESULTS: We recruited 193 patients with any clinical indication for whole body [18F]-FDG-PET/CT. BHB level was measured with a point-of-care device. Maximal myocardial standardized uptake value using lean body mass (SULmax) was measured from eight circular regions of interest with 1 cm circumference and background from left ventricular blood pool. Correlations SULmax and point-of-care measured BHB were analysed. The ability of BHB test to predict adequate suppression was evaluated with receiver operating characteristic analysis. Liver and spleen attenuation in computed tomography were measured to assess the presence of fatty liver. BHB level correlated with myocardial uptake and, using a cut-off value of 0.35 mmol/L to predict adequate myocardial suppression, we reached specificity of 90% and sensitivity of 56%. Other variables to predict adequate suppression were diabetes, obesity, ketogenic diet and fatty liver. Using information attainable before imaging, we created a pretest probability calculator of inadequate myocardial glucose metabolism suppression. The area under the curve for BHB test alone was 0.802 and was 0.857 for the pretest calculator (p = 0.319).
CONCLUSIONS: BHB level measured with a point-of-care device is useful in predicting adequate myocardial glucose metabolism suppression. More detailed assessment of other factors potentially contributing to cardiac metabolism is needed.

Keywords:  BHB; glucose metabolism; myocardial inflammation; myocardium; β‐hydroxybutyrate

DOI:  https://doi.org/10.1111/cpf.12881
J Cereb Blood Flow Metab. 2024 Apr 11. 271678X241245486

Neuroprotective effects of lactate and ketone bodies in acute brain injury.

Guillaume Plourde, Hélène Roumes, Laurent Suissa, Lorenz Hirt, Émilie Doche, Luc Pellerin, Anne-Karine Bouzier-Sore, Hervé Quintard.

  The goal of neurocritical care is to prevent and reverse the pathologic cascades of secondary brain injury by optimizing cerebral blood flow, oxygen supply and substrate delivery. While glucose is an essential energetic substrate for the brain, we frequently observe a strong decrease in glucose delivery and/or a glucose metabolic dysregulation following acute brain injury. In parallel, during the last decades, lactate and ketone bodies have been identified as potential alternative fuels to provide energy to the brain, both under physiological conditions and in case of glucose shortage. They are now viewed as integral parts of brain metabolism. In addition to their energetic role, experimental evidence also supports their neuroprotective properties after acute brain injury, regulating in particular intracranial pressure control, decreasing ischemic volume, and leading to an improvement in cognitive functions as well as survival. In this review, we present preclinical and clinical evidence exploring the mechanisms underlying their neuroprotective effects and identify research priorities for promoting lactate and ketone bodies use in brain injury.

Keywords:  Alternative brain fuels; TBI; brain metabolism; hypoxia; ketone bodies; lactate; neuroprotection; stroke

DOI:  https://doi.org/10.1177/0271678X241245486
Front Cardiovasc Med. 2024 ;11 1375400

Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.

Yue Zeng, Yilang Li, Wenyue Jiang, Ning Hou.

  Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.

Keywords:  cardiac function; diabetic cardiomyopathy; fatty acid oxidation; glucotoxicity; heart failure; metabolism

DOI:  https://doi.org/10.3389/fcvm.2024.1375400
Int J Mol Sci. 2024 Apr 04. pii: 4025. [Epub ahead of print]25(7):

Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1).

Stéphanie Paradis, Anne-Laure Charles, Margherita Giannini, Alain Meyer, Anne Lejay, Samy Talha, Gilles Laverny, Anne Charloux, Bernard Geny.

  Peripheral arterial disease (PAD) strikes more than 200 million people worldwide and has a severe prognosis by potentially leading to limb amputation and/or death, particularly in older patients. Skeletal muscle mitochondrial dysfunctions and oxidative stress play major roles in this disease in relation with ischemia-reperfusion (IR) cycles. Mitochondrial dynamics through impairment of fission-fusion balance may contribute to skeletal muscle pathophysiology, but no data were reported in the setting of lower-limb IR despite the need for new therapeutic options. We, therefore, investigated the potential protective effect of mitochondrial division inhibitor-1 (mDivi-1; 50 mg/kg) in young (23 weeks) and old (83 weeks) mice submitted to two-hour ischemia followed by two-hour reperfusion on systemic lactate, muscle mitochondrial respiration and calcium retention capacity, and on transcripts specific for oxidative stress and mitochondrial dynamics. At the systemic levels, an IR-related increase in circulating lactate was still major despite mDivi-1 use (+305.9% p < 0.0001, and +269.4% p < 0.0001 in young and old mice, respectively). Further, IR-induced skeletal muscle mitochondrial dysfunctions (more severely impaired mitochondrial respiration in old mice (OXPHOS CI state, -68.2% p < 0.0001 and -84.9% p < 0.0001 in 23- and 83-week mice) and reduced calcium retention capacity (-46.1% p < 0.001 and -48.2% p = 0.09, respectively) were not corrected by mDivi-1 preconditioning, whatever the age. Further, mDivi-1 treatment did not oppose superoxide anion production (+71.4% p < 0.0001 and +37.5% p < 0.05, respectively). At the transcript level, markers of antioxidant enzymes (SOD 1, SOD 2, catalase, and GPx) and fission markers (Drp1, Fis) remained unchanged or tended to be decreased in the ischemic leg. Fusion markers such as mitofusin 1 or 2 decreased significantly after IR in both groups. In conclusion, aging enhanced the deleterious effects or IR on muscle mitochondrial respiration, and in this setting of lower-limb IR, mDivi-1 failed to protect the skeletal muscle both in young and old mice.

Keywords:  aging; ischemia reperfusion; lactate; mitochondria; mitochondrial dynamics; muscle; peripheral arterial disease; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms25074025
JAMA. 2024 Apr 12.

Study Examines Intermittent Fasting and Cardiovascular Mortality.

Emily Harris.

DOI: https://doi.org/10.1001/jama.2024.5158
Exp Physiol. 2024 Apr 09.

Skeletal muscle mitochondrial correlates of critical power and W' in healthy active individuals.

Donald L Peden, Robert Rogers, Emma A Mitchell, Suzanne M Taylor, Stephen J Bailey, Richard A Ferguson.

  The asymptote (critical power; CP) and curvature constant (W') of the hyperbolic power-duration relationship can predict performance within the severe-intensity exercise domain. However, the extent to which these parameters relate to skeletal muscle mitochondrial content and respiratory function is not known. Fifteen males (peak O2 uptake, 52.2 ± 8.7 mL kg-1 min-1; peak work rate, 366 ± 40 W; and gas exchange threshold, 162 ± 41 W) performed three to five constant-load tests to task failure for the determination of CP (246 ± 44 W) and W' (18.6 ± 4.1 kJ). Skeletal muscle biopsies were obtained from the vastus lateralis to determine citrate synthase (CS) activity, as a marker of mitochondrial content, and the ADP-stimulated respiration (P) and maximal electron transfer (E) through mitochondrial complexes (C) I-IV. The CP was positively correlated with CS activity (absolute CP, r = 0.881, P < 0.001; relative CP, r = 0.751, P = 0.001). The W' was not correlated with CS activity (P > 0.05). Relative CP was positively correlated with mass-corrected CI + IIE (r = 0.659, P = 0.038), with absolute CP being inversely correlated with CS activity-corrected CIVE (r = -0.701, P = 0.024). Relative W' was positively correlated with CS activity-corrected CI + IIP (r = 0.713, P = 0.021) and the phosphorylation control ratio (r = 0.661, P = 0.038). There were no further correlations between CP or W' and mitochondrial respiratory variables. These findings support the assertion that skeletal muscle mitochondrial oxidative capacity is positively associated with CP and that this relationship is strongly determined by mitochondrial content.

Keywords:  citrate synthase activity; high‐resolution respirometry; mitochondrial content; mitochondrial function; power–duration relationship; severe‐intensity exercise

DOI:  https://doi.org/10.1113/EP091835
Cells. 2024 Mar 26. pii: 574. [Epub ahead of print]13(7):

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy.

Silvia Rosanna Casati, Davide Cervia, Paulina Roux-Biejat, Claudia Moscheni, Cristiana Perrotta, Clara De Palma.

  Duchenne muscular dystrophy (DMD) is a genetic progressive muscle-wasting disorder that leads to rapid loss of mobility and premature death. The absence of functional dystrophin in DMD patients reduces sarcolemma stiffness and increases contraction damage, triggering a cascade of events leading to muscle cell degeneration, chronic inflammation, and deposition of fibrotic and adipose tissue. Efforts in the last decade have led to the clinical approval of novel drugs for DMD that aim to restore dystrophin function. However, combination therapies able to restore dystrophin expression and target the myriad of cellular events found impaired in dystrophic muscle are desirable. Muscles are higher energy consumers susceptible to mitochondrial defects. Mitochondria generate a significant source of reactive oxygen species (ROS), and they are, in turn, sensitive to proper redox balance. In both DMD patients and animal models there is compelling evidence that mitochondrial impairments have a key role in the failure of energy homeostasis. Here, we highlighted the main aspects of mitochondrial dysfunction and oxidative stress in DMD and discussed the recent findings linked to mitochondria/ROS-targeted molecules as a therapeutic approach. In this respect, dual targeting of both mitochondria and redox homeostasis emerges as a potential clinical option in DMD.

Keywords:  DMD therapies; Duchenne muscular dystrophy; antioxidant defense; mitochondria; mitophagy; oxidative stress; redox homeostasis; skeletal muscle

DOI:  https://doi.org/10.3390/cells13070574
Front Nutr. 2024 ;11 1368966

Mechanisms of body fat distribution and gluteal-femoral fat protection against metabolic disorders.

Maha Alser, Khaled Naja, Mohamed A Elrayess.

  Obesity is a major health problem that affects millions of individuals, and it is associated with metabolic diseases including insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular diseases (CVDs). However, Body fat distribution (BFD) rather than crude obesity is now considered as a more accurate factor associated with these diseases. The factors affecting BFD vary, from genetic background, epigenetic factors, ethnicity, aging, hormonal changes, to lifestyle and medication consumptions. The main goal of controlling BFD comes from the fact that fat accumulation in different depots has a different effect on the overall health and metabolic health of individuals. It is well established that fat storage in the abdominal visceral depot is associated with metabolic disorder occurrence, while gluteal-femoral subcutaneous fat depot seems to be protective against these diseases. In this paper, we will summarize the factors affecting fat distribution. Then, we will present evidence connecting gluteal-femoral fat depot with protection against metabolic disorders including IR, T2D, and CVDs. Finally, we will list the suggested mechanisms that lead to this protective effect. The abstract is visualized in Graphical Abstract.

Keywords:  body fat distribution; cardiovascular diseases; metabolic protection; prediabetes; thigh fat; type 2 diabetes

DOI:  https://doi.org/10.3389/fnut.2024.1368966
Nutrients. 2024 Mar 28. pii: 995. [Epub ahead of print]16(7):

Calorie Restriction Using High-Fat/Low-Carbohydrate Diet Suppresses Liver Fat Accumulation and Pancreatic Beta-Cell Dedifferentiation in Obese Diabetic Mice.

Xiao Lei, Emi Ishida, Satoshi Yoshino, Shunichi Matsumoto, Kazuhiko Horiguchi, Eijiro Yamada.

  In diabetes, pancreatic β-cells gradually lose their ability to secrete insulin with disease progression. β-cell dysfunction is a contributing factor to diabetes severity. Recently, islet cell heterogeneity, exemplified by β-cell dedifferentiation and identified in diabetic animals, has attracted attention as an underlying molecular mechanism of β-cell dysfunction. Previously, we reported β-cell dedifferentiation suppression by calorie restriction, not by reducing hyperglycemia using hypoglycemic agents (including sodium-glucose cotransporter inhibitors), in an obese diabetic mice model (db/db). Here, to explore further mechanisms of the effects of food intake on β-cell function, db/db mice were fed either a high-carbohydrate/low-fat diet (db-HC) or a low-carbohydrate/high-fat diet (db-HF) using similar calorie restriction regimens. After one month of intervention, body weight reduced, and glucose intolerance improved to a similar extent in the db-HC and db-HF groups. However, β-cell dedifferentiation did not improve in the db-HC group, and β-cell mass compensatory increase occurred in this group. More prominent fat accumulation occurred in the db-HC group livers. The expression levels of genes related to lipid metabolism, mainly regulated by peroxisome proliferator-activated receptor α and γ, differed significantly between groups. In conclusion, the fat/carbohydrate ratio in food during calorie restriction in obese mice affected both liver lipid metabolism and β-cell dedifferentiation.

Keywords:  calorie restriction; carbohydrate/fat ratio; db/db mice; diabetes; dyslipidemia; metabolic dysfunction associated steatotic liver disease; obesity; pancreatic β cells; peroxisome proliferator-activated receptor; β-cell dedifferentiation

DOI:  https://doi.org/10.3390/nu16070995
J Clin Med. 2024 Apr 08. pii: 2150. [Epub ahead of print]13(7):

Association of Obesity with Telomere Length in Human Sperm.

Efthalia Moustakli, Athanasios Zikopoulos, Charikleia Skentou, Stefanos Dafopoulos, Sofoklis Stavros, Konstantinos Dafopoulos, Peter Drakakis, Ioannis Georgiou, Athanasios Zachariou.

  Background: Telomere attrition and mitochondrial dysfunction are two fundamental aspects of aging. Calorie restriction (CR) is the best strategy to postpone aging since it can enhance telomere attrition, boost antioxidant capacity, and lower the generation of reactive oxygen species (ROS). Since ROS is produced by mitochondria and can readily travel to cell nuclei, it is thought to be a crucial molecule for information transfer between mitochondria and cell nuclei. Important variables that affect the quality and functionality of sperm and may affect male reproductive health and fertility include telomere length, mitochondrial content, and the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA). Telomere damage results from mitochondrial failure, whereas nuclear DNA remains unaffected. This research aims to investigate potential associations between these three variables and how they might relate to body mass index. Methods: Data were collected from 82 men who underwent IVF/ICSI at the University Hospital of Ioannina's IVF Unit in the Obstetrics and Gynecology Department. Evaluations included sperm morphology, sperm count, sperm motility, and participant history. To address this, male participants who were categorized into three body mass index (ΒΜΙ) groups-normal, overweight, and obese-had their sperm samples tested. Results: For both the normal and overweight groups, our results show a negative connection between relative telomere length and ΒΜI. As an illustration of a potential connection between mitochondrial health and telomere maintenance, a positive correlation was found for the obese group. Only the obese group's results were statistically significant (p < 0.05). More evidence that longer telomeres are associated with lower mitochondrial content can be found in the negative connection between telomere length and mitochondrial content in both the normal and overweight groups. However, the obese group showed a positive association. The data did not reach statistical significance for any of the three groups. These associations may affect sperm quality since telomere length and mitochondrial concentration are indicators of cellular integrity and health. Moreover, the ratio of mtDNA to nDNA was positively correlated with the relative telomere lengths of the obese group, but negatively correlated with the normal and overweight groups. In every group that was studied, the results were not statistically significant. According to this, male fertility may be negatively impacted by an imbalance in the copy number of the mitochondrial genome compared to the nuclear DNA in sperm. Conclusions: Essentially, the goal of our work is to determine whether mitochondria and telomere length in human sperm interact. Understanding these connections may aid in the explanation of some male infertility causes and possibly contribute to the creation of new treatment modalities for problems pertaining to reproductive health. The functional implications of these connections and their applications in therapeutic settings require further investigation.

Keywords:  IVF/ICSI; body mass index; male infertility; mitochondria; oxidation; spermatozoa; telomere length; telomeres

DOI:  https://doi.org/10.3390/jcm13072150
J Clin Endocrinol Metab. 2024 Apr 13. pii: dgae237. [Epub ahead of print]

Substituting carbohydrate at lunch for added protein increases fat oxidation during subsequent exercise in healthy males.

Tommy Slater, William J A Mode, Louise C Bonnard, Cian Sweeney, Mark P Funnell, Harry A Smith, John Hough, Ruth M James, Ian Varley, Craig Sale, James A Betts, Lewis J James, David J Clayton.

  CONTEXT: How pre-exercise meal composition influences metabolic and health responses to exercise later in the day is currently unclear.OBJECTIVE: Examine the effects of substituting carbohydrate for protein at lunch on subsequent exercise metabolism, appetite, and energy intake.
METHODS: Twelve healthy males completed three trials in randomized, counterbalanced order. Following a standardized breakfast (779 ± 66 kcal; ∼08:15), participants consumed a lunch (1186 ± 140 kcal; ∼13:15) containing either 0.2 g·kg-1 carbohydrate and ∼2 g·kg-1 protein (LO-CARB), 2 g·kg-1 carbohydrate and ∼0.4 g·kg-1 protein (HI-CARB), or fasted (FAST). Participants later cycled at ∼60% V̇O2peak for 1 h (∼16:15) and post-exercise ad-libitum energy intake was measured (∼18:30). Substrate oxidation, subjective appetite, and plasma concentrations of glucose, insulin, non-esterified fatty acids (NEFA), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and acylated ghrelin (AG) were measured for 5 h post-lunch.
RESULTS: Fat oxidation was greater during FAST (+11.66 ± 6.63 g) and LO-CARB (+8.00 ± 3.83 g) than HI-CARB (p < 0.001), with FAST greater than LO-CARB (+3.67 ± 5.07 g; p < 0.05). NEFA were lowest in HI-CARB and highest in FAST, with insulin demonstrating the inverse response (all p < 0.01). PYY and GLP-1 demonstrated a stepwise pattern, with LO-CARB greatest and FAST lowest (all p < 0.01). AG was lower during HI-CARB and LO-CARB versus FAST (p < 0.01). Energy intake in LO-CARB was lower than FAST (-383 ± 233 kcal; p < 0.001) and HI-CARB (-313 ± 284 kcal; p < 0.001).
CONCLUSION: Substituting carbohydrate for protein in a pre-exercise lunch increased fat oxidation, suppressed subjective and hormonal appetite, and reduced post-exercise energy intake.

Keywords:  Carbohydrate restriction; appetite hormones; energy intake; exercise metabolism; fasting; protein

DOI:  https://doi.org/10.1210/clinem/dgae237
Fluids Barriers CNS. 2024 Apr 08. 21(1): 33

Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation.

Stéphanie Chasseigneaux, Véronique Cochois-Guégan, Lucas Lecorgne, Murielle Lochus, Sophie Nicolic, Corinne Blugeon, Laurent Jourdren, David Gomez-Zepeda, Stefan Tenzer, Sylvia Sanquer, Valérie Nivet-Antoine, Marie-Claude Menet, Jean-Louis Laplanche, Xavier Declèves, Salvatore Cisternino, Bruno Saubaméa.

  BACKGROUND: The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters.METHODS: We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion.
RESULTS: Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting.
CONCLUSIONS: Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain.

Keywords:  Blood-brain barrier; Endothelial cells; Fasting; MCT1; PPAR δ

DOI:  https://doi.org/10.1186/s12987-024-00526-8
Cancers (Basel). 2024 Apr 02. pii: 1399. [Epub ahead of print]16(7):

Inhibition of Carbohydrate Metabolism Potentiated by the Therapeutic Effects of Oxidative Phosphorylation Inhibitors in Colon Cancer Cells.

Lichao Guo, Baochen Zhang, Wen Zhang, Yanqi Xie, Xi Chen, Xueke Sun, David S Watt, Chunming Liu, H Peter Spielmann, Xifu Liu.

  Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure-activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy.

Keywords:  OXPHOS; colorectal cancer; glycolysis; isoflavonoid; ketogenic diet; mitochondria complex I

DOI:  https://doi.org/10.3390/cancers16071399
Front Pharmacol. 2024 ;15 1341333

The effect of oral butyrate on colonic short-chain fatty acid transporters and receptors depends on microbial status.

Karla Vagnerová, Tomáš Hudcovic, Martin Vodička, Peter Ergang, Petra Klusoňová, Petra Petr Hermanová, Dagmar Šrůtková, Jiří Pácha.

  Butyrate, a metabolite produced by gut bacteria, has demonstrated beneficial effects in the colon and has been used to treat inflammatory bowel diseases. However, the mechanism by which butyrate operates remains incompletely understood. Given that oral butyrate can exert either a direct impact on the gut mucosa or an indirect influence through its interaction with the gut microbiome, this study aimed to investigate three key aspects: (1) whether oral intake of butyrate modulates the expression of genes encoding short-chain fatty acid (SCFA) transporters (Slc16a1, Slc16a3, Slc16a4, Slc5a8, Abcg2) and receptors (Hcar2, Ffar2, Ffar3, Olfr78, Olfr558) in the colon, (2) the potential involvement of gut microbiota in this modulation, and (3) the impact of oral butyrate on the expression of colonic SCFA transporters and receptors during colonic inflammation. Specific pathogen-free (SPF) and germ-free (GF) mice with or without DSS-induced inflammation were provided with either water or a 0.5% sodium butyrate solution. The findings revealed that butyrate decreased the expression of Slc16a1, Slc5a8, and Hcar2 in SPF but not in GF mice, while it increased the expression of Slc16a3 in GF and the efflux pump Abcg2 in both GF and SPF animals. Moreover, the presence of microbiota was associated with the upregulation of Hcar2, Ffar2, and Ffar3 expression and the downregulation of Slc16a3. Interestingly, the challenge with DSS did not alter the expression of SCFA transporters, regardless of the presence or absence of microbiota, and the effect of butyrate on the transporter expression in SPF mice remained unaffected by DSS. The expression of SCFA receptors was only partially affected by DSS. Our results indicate that (1) consuming a relatively low concentration of butyrate can influence the expression of colonic SCFA transporters and receptors, with their expression being modulated by the gut microbiota, (2) the effect of butyrate does not appear to result from direct substrate-induced regulation but rather reflects an indirect effect associated with the gut microbiome, and (3) acute colon inflammation does not lead to significant changes in the transcriptional regulation of most SCFA transporters and receptors, with the effect of butyrate in the inflamed colon remaining intact.

Keywords:  butyrate; butyrate receptors; butyrate transporters; colitis; dextran sulfate; germ-free (GF); microbiota; short chain fatty acid (SCFA)

DOI:  https://doi.org/10.3389/fphar.2024.1341333
Sci Rep. 2024 04 08. 14(1): 8176

Curcumin regulates autophagy through SIRT3-SOD2-ROS signaling pathway to improve quadriceps femoris muscle atrophy in KOA rat model.

Hua Ye, Yi Long, Jia-Ming Yang, Yan-Lin Wu, Ling-Yan Dong, Yan-Biao Zhong, Yun Luo, Mao-Yuan Wang.

  Knee osteoarthritis (KOA) usually leads to quadriceps femoris atrophy, which in turn can further aggravate the progression of KOA. Curcumin (CUR) has anti-inflammatory and antioxidant effects and has been shown to be a protective agent for skeletal muscle. CUR has been shown to have a protective effect on skeletal muscle. However, there are no studies related to whether CUR improves KOA-induced quadriceps femoris muscle atrophy. We established a model of KOA in rats. Rats in the experimental group were fed CUR for 5 weeks. Changes in autophagy levels, reactive oxygen species (ROS) levels, and changes in the expression of the Sirutin3 (SIRT3)-superoxide dismutase 2 (SOD2) pathway were detected in the quadriceps femoris muscle of rats. KOA led to quadriceps femoris muscle atrophy, in which autophagy was induced and ROS levels were increased. CUR increased SIRT3 expression, decreased SOD2 acetylation and ROS levels, inhibited the over-activation of autophagy, thereby alleviating quadriceps femoris muscle atrophy and improving KOA. CUR has a protective effect against quadriceps femoris muscle atrophy, and KOA is alleviated after improvement of quadriceps femoris muscle atrophy, with the possible mechanism being the reduction of ROS-induced autophagy via the SIRT3-SOD2 pathway.

Keywords:  Autophagy; Curcumin; Knee osteoarthritis; Quadriceps femoris muscle

DOI:  https://doi.org/10.1038/s41598-024-58375-2
bioRxiv. 2024 Mar 29. pii: 2024.03.25.586170. [Epub ahead of print]

MITOCHONDRIA-ASSOCIATED MEMBRANES ARE NOT ALTERED IN IMMUNE CELLS IN T2D.

Samantha N Hart, Raji Lenin, Jamie Sturgill, Philip A Kern, Barbara Nikolajczyk.

Metabolism research is increasingly recognizing the contributions of organelle crosstalk to metabolic regulation. Mitochondria-associated membranes (MAMs), which are structures connecting the mitochondria and endoplasmic reticulum (ER), are critical in a myriad of cellular functions linked to cellular metabolism. MAMs control calcium signaling, mitochondrial transport, redox balance, protein folding/degradation, and in some studies, metabolic health. The possibility that MAMs drive changes in cellular function in individuals with Type 2 Diabetes (T2D) is controversial. Although disruptions in MAMs that change the distance between the mitochondria and ER, MAM protein composition, or disrupt downstream signaling, can perpetuate inflammation, one key trait of T2D. However, the full scope of this structure's role in immune cell health and thus T2D-associated inflammation remains unknown. We show that human immune cell MAM proteins and their associated functions are not altered by T2D and thus unlikely to contribute to metaflammation.

DOI: https://doi.org/10.1101/2024.03.25.586170