bims-mimcad 2024-12-29 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–12–29
eleven papers selected by
Henver Brunetta, Karolinska Institutet

Cardiomyocyte STIM1 downregulation exacerbates post-Myocardial Infarction remodeling by dysregulating mitochondrial ultrastructure and metabolic signaling.
NRH, a potent NAD+ enhancer, improves glucose homeostasis and lipid metabolism in diet-induced obese mice though an active adenosine kinase pathway.
Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.
Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes.
Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
Cardiovascular and Metabolic Effects of Modulating Circulating Ketone Bodies With 1,3-Butanediol in Patients With Heart Failure With Reduced Ejection Fraction.
In-depth Characterization of S-Glutathionylation in Ventricular Myosin Light Chain 1 Across Species by Top-Down Proteomics.
Prediction of metabolic subphenotypes of type 2 diabetes via continuous glucose monitoring and machine learning.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
High-resolution DNA methylation changes reveal biomarkers of heart failure with preserved ejection fraction versus reduced ejection fraction.
SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.

bioRxiv. 2024 Dec 09. pii: 2024.12.05.625436. [Epub ahead of print]

Cardiomyocyte STIM1 downregulation exacerbates post-Myocardial Infarction remodeling by dysregulating mitochondrial ultrastructure and metabolic signaling.

Marine Cacheux, Juan Velasco, Xiaohong Wu, Benjamin Strauss, Fadi G Akar.

Background: Loss of stromal interaction molecule 1 (STIM1) expression in smooth muscle cells protects against ischemia-reperfusion (I/R) injury. Whether and how decreased STIM1 expression in cardiomyocytes (CM) impacts cardiac remodeling in response to I/R injury remains unknown.
Objective: To examine mechanisms by which decreased CM-STIM1 expression in the adult heart modulates cardiac function before and after I/R injury.
Methods: 8-week old mice underwent cardiotropic AAV9-mediated gene transfer of shRNA directed against STIM1 (shSTIM1). Control (Ctrl) mice underwent shRNA luciferase or PBS injections. Ctrl and shSTIM1 mice were then challenged by 30-min coronary occlusion to induce MI, in-vivo . Mechanical, structural and electrophysiological (EP) properties were compared 1-week following MI. In a second cohort of mice, the impact of CM-STIM1 knockdown per se on upstream metabolic signaling, mitochondrial ultrastructure, and electrophysiological properties were studied.
Results: CM-STIM1 expression was markedly decreased in shSTIM1 vs Ctrl hearts. Challenge with in-vivo I/R injury resulted in more pronounced (p<0.0001) LV dysfunction indexed by % drop in fractional shortening in shSTIM1 (44.3%) vs Ctrl (12.2%) hearts 1-week post-MI. Similarly, post-MI structural remodeling and the extent of fibrosis were more severe in shSTIM1 vs Ctrl despite comparable infarct size (p=0.514). Consistently, shSTIM1 exhibited greater impairment in post-MI EP function including predisposition to spatially-discordant action potential alternans. To understand mechanisms underlying this differential remodeling, we examined the impact of CM-STIM1 downregulation on mitochondrial ultrastructure and regulation by metabolic signaling. Quantification of mitochondrial morphology revealed smaller, more rounded mitochondria caused by CM-STIM1 downregulation per se . Underlying these changes was a marked (by 55%, p=0.0057) increase in phosphorylated (p)DRP1 at S616 along with reduced OPA1 expression. Mitochondrial alterations were associated with significant decreases in AMPK downstream signaling with loss of phosphorylated-to-total Raptor and ACC expression in shSTIM1-vs-Ctrl hearts consistent with impaired fatty acid oxidation. These MI-independent metabolic alterations coincided with higher pro-arrhythmic vulnerability under conditions of elevated heart rate.
Conclusions: Our findings reveal that decreased CM-STIM1 expression exacerbates post-MI remodeling likely by altering metabolic processes and mitochondrial network dynamics.Functionally, STIM1-dependent mitochondrial alterations impact EP function during conditions of elevated heart rate even without the confounding influence of MI.

DOI: https://doi.org/10.1101/2024.12.05.625436
Metabolism. 2024 Dec 20. pii: S0026-0495(24)00338-X. [Epub ahead of print]164 156110

NRH, a potent NAD+ enhancer, improves glucose homeostasis and lipid metabolism in diet-induced obese mice though an active adenosine kinase pathway.

Xinliu Zeng, Yongjie Wang, Karina Farias, Andrew Rappa, Christine Darko, Anthony Sauve, Qingxia Huang, Laura C Alonso, Yue Yang.

   AIMS: NAD+ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD+ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD+ synthesis.
METHODS: Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD+ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.
RESULTS: NRH entered tissues unassisted and was rapidly metabolized for NAD+ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD+ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.
CONCLUSION: This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD+ enhancement.

Keywords:  Adenosine kinase; Hyperlipidemia; NAD(+); NRH; Obesity; Sirtuin; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.metabol.2024.156110
Muscle Nerve. 2024 Dec 23.

Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.

Benjamin Chatel, Isabelle Varlet, Augustin C Ogier, Emilie Pecchi, Monique Bernard, Julien Gondin, Håkan Westerblad, David Bendahan, Charlotte Gineste.

   INTRODUCTION AND AIMS: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
METHODS: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy.
RESULTS: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice.
DISCUSSION: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.

Keywords:  force production; mitochondrial function; muscle disease; pharmacological agent; preclinical model

DOI:  https://doi.org/10.1002/mus.28315
bioRxiv. 2024 Dec 10. pii: 2024.12.09.626845. [Epub ahead of print]

Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes.

Melissa D Lempicki, Ryan J Garrigues, Tonya N Zeczycki, Brandon L Garcia, Thurl E Harris, Akshaya K Meher.

Glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorbing excess blood glucose, failure of which promotes hyperglycemia. Matrix metalloproteinases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, and surprisingly, it is unknown if they can directly target GLUT4 on the adipocyte surface and impair glucose absorption. We identified MMP2 as the highly active gelatinase, a class of MMP, in the gonadal WAT of high-fat diet-induced obese mice. In vitro, metabolic studies in 3T3-L1 adipocytes revealed MMP2 attenuated glucose absorption and glycolysis, which were recovered by an MMP2 inhibitor. In silico structural analysis using AlphaFold identified a putative MMP2 cleavage site on the extracellular domain of GLUT4. Further, in a substrate competition assay, a peptide mimicking the MMP2 cleavage motif on GLUT4 attenuated the cleavage of an MMP substrate by MMP2. Altogether, our results suggest a novel mechanism of impaired glucose absorption by adipocytes, which may contribute to hyperglycemia during obesity.

DOI: https://doi.org/10.1101/2024.12.09.626845
Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01147-X. [Epub ahead of print]227 619-628

Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.

Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi.

  The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.

Keywords:  Exercise; Mitochondria; Mitochondrial-derived peptides; Skeletal muscle; The mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-C)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.038
J Am Heart Assoc. 2024 Dec 24. e038461

Cardiovascular and Metabolic Effects of Modulating Circulating Ketone Bodies With 1,3-Butanediol in Patients With Heart Failure With Reduced Ejection Fraction.

Halvor Guldbrandsen, Nigopan Gopalasingam, Kristian Hylleberg Christensen, Oskar Kjærgaard Hørsdal, Roni Nielsen, Henrik Wiggers, Kristoffer Berg-Hansen.

   BACKGROUND: Oral treatment with the exogenous ketone body 3-hydroxybutyrate improves cardiac function in patients with heart failure with reduced ejection fraction, but ketosis is limited to 3 to 4 hours. Treatment with (R)-1,3-butanediol (BD) provides prolonged ketosis in healthy controls, but the hemodynamic and metabolic profile is unexplored in patients with heart failure with reduced ejection fraction.
METHODS AND RESULTS: This was a randomized, single-blind, placebo-controlled, crossover study. Transthoracic echocardiography and venous blood samples were performed at baseline and hourly for 6 hours after an oral dose of BD (0.5 g/kg) or taste-matched placebo. The primary end point was the average between-treatment difference in cardiac output during the 6-hour period after intake. Secondary end points were stroke volume, heart rate, left ventricular ejection fraction, circulating 3-hydroxybutyrate, and free fatty acids. Twelve patients with heart failure with reduced ejection fraction were included. BD treatment provided significant increase in circulating 3-hydroxybutyrate by 1400 μmol/L (95% CI, 1262-1538 μmol/L, P<0.001) and increased cardiac output by 0.9 L/min (95% CI, 0.7-1.1 L/min, P<0.001) compared with placebo. Stroke volume increased by 15 mL (95% CI, 11-19 mL, P<0.001), and heart rate remained similar between treatments (P=0.150). Left ventricular ejection fraction increased by 3 percentage points (95% CI, 1-4 percentage points, P<0.001). Global longitudinal strain improved (P<0.001). Left ventricular contractility estimates increased after BD intake, and parameters of afterload were reduced. Finally, free fatty acids and glucose levels decreased.
CONCLUSIONS: Oral dosing of BD led to prolonged ketosis and cardiovascular and metabolic benefits in patients with heart failure with reduced ejection fraction. Treatment with BD is an attractive option to achieve beneficial effects from sustained therapeutic ketosis.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05768100.

Keywords:  cardiac output; echocardiography; heart failure; hemodynamics; ketone bodies

DOI:  https://doi.org/10.1161/JAHA.124.038461
bioRxiv. 2024 Dec 12. pii: 2024.12.11.628048. [Epub ahead of print]

In-depth Characterization of S-Glutathionylation in Ventricular Myosin Light Chain 1 Across Species by Top-Down Proteomics.

Emily A Chapman, Holden T Rogers, Zhan Gao, Hsin-Ju Chan, Francisco J Alvarado, Ying Ge.

S-glutathionylation (SSG) is increasingly recognized as a critical signaling mechanism in the heart, yet SSG modifications in cardiac sarcomeric proteins remain understudied. Here we identified SSG of the ventricular isoform of myosin light chain 1 (MLC-1v) in human, swine, and mouse cardiac tissues using top-down mass spectrometry (MS)-based proteomics. Our results enabled the accurate identification, quantification, and site-specific localization of SSG in MLC-1v across different species. Notably, the endogenous SSG of MLC-1v was observed in human and swine cardiac tissues but not in mice. Treating non-reduced cardiac tissue lysates with GSSG elevated MLC-1v SSG levels across all three species.

DOI: https://doi.org/10.1101/2024.12.11.628048
Nat Biomed Eng. 2024 Dec 23.

Prediction of metabolic subphenotypes of type 2 diabetes via continuous glucose monitoring and machine learning.

Ahmed A Metwally, Dalia Perelman, Heyjun Park, Yue Wu, Alokkumar Jha, Seth Sharp, Alessandra Celli, Ekrem Ayhan, Fahim Abbasi, Anna L Gloyn, Tracey McLaughlin, Michael P Snyder.

The classification of type 2 diabetes and prediabetes does not consider heterogeneity in the pathophysiology of glucose dysregulation. Here we show that prediabetes is characterized by metabolic heterogeneity, and that metabolic subphenotypes can be predicted by the shape of the glucose curve measured via a continuous glucose monitor (CGM) during standardized oral glucose-tolerance tests (OGTTs) performed in at-home settings. Gold-standard metabolic tests in 32 individuals with early glucose dysregulation revealed dominant or co-dominant subphenotypes (muscle or hepatic insulin-resistance phenotypes in 34% of the individuals, and β-cell-dysfunction or impaired-incretin-action phenotypes in 40% of them). Machine-learning models trained with glucose time series from OGTTs from the 32 individuals predicted the subphenotypes with areas under the curve (AUCs) of 95% for muscle insulin resistance, 89% for β-cell deficiency and 88% for impaired incretin action. With CGM-generated glucose curves obtained during at-home OGTTs, the models predicted the muscle-insulin-resistance and β-cell-deficiency subphenotypes of 29 individuals with AUCs of 88% and 84%, respectively. At-home identification of metabolic subphenotypes via a CGM may aid the risk stratification of individuals with early glucose dysregulation.

DOI: https://doi.org/10.1038/s41551-024-01311-6
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Basic Res Cardiol. 2024 Dec 27.

High-resolution DNA methylation changes reveal biomarkers of heart failure with preserved ejection fraction versus reduced ejection fraction.

Giuditta Benincasa, Mark E Pepin, Vincenzo Russo, Francesco Cacciatore, Michele D'Alto, Paola Argiento, Emanuele Romeo, Rosaria Chiappetti, Nunzia Laezza, Adam R Wende, Gabriele G Schiattarella, Enrico Coscioni, Antonietta La Montagna, Cristiano Amarelli, Ciro Maiello, Paolo Golino, Gianluigi Condorelli, Claudio Napoli.

  Novel biomarkers are needed to better identify-and distinguish-heart failure with preserved ejection fraction (HFpEF) from other clinical phenotypes. The goal of our study was to identify epigenetic-sensitive biomarkers useful to a more accurate diagnosis of HFpEF. We performed a network-oriented genome-wide DNA methylation study of circulating CD4+ T lymphocytes isolated from peripheral blood using reduced representation bisulfite sequencing (RRBS) in two cohorts (i.e., discovery/validation) each of both male and female patients with HFpEF (n = 12/10), HF with reduced EF (HFrEF; n = 7/5), and volunteers lacking clinical evidence of HF (CON; n = 7/5). RRBS is the gold-standard platform for measuring genome-wide DNA methylation changes at single-cytosine resolution in hypothesis-generating studies. We identified three hypomethylated HFpEF-specific differentially methylated positions (DMPs) associated with FOXB1, ELMOD1, and DGKH genes wherein ROC curve analysis revealed that increased expression levels had a reasonable diagnostic performance in predicting HFpEF (AUC ≥ 0.8, p < 0.05). Network analysis identified additional three genes including JUNB (p = 0.037), SETD7 (p = 0.003), and MEF2D (p = 0.0001) which were significantly higher in HFpEF vs. HFrEF patients. ROC curve analysis showed that integrating the functional H2FPEF classification with the expression levels of the FOXB1, ELMOD1, and DGKH as well as the JUNB, SETD7, and MEF2D genes improved diagnostic accuracy, with AUC = 0.8 (p < 0.0001) as compared to H2FPEF score alone (p > 0.05). Besides, increased expression levels of SETD7-RELA-IL6 axis significantly discriminated overweight/obese HFpEF vs. HFrEF patients (AUC = 1; p = 0.001, p = 0.006, p = 0.006, respectively). We support an emerging dogma that indirect epigenetic testing via high-resolution RRBS methylomics represents a non-invasive tool that may enable easier access to both diagnostic and mechanistic insights of HFpEF. An epigenetic-oriented dysregulation of network-derived SETD7-RELA-IL6 axis in circulating CD4+ T lymphocytes may drive pro-inflammatory responses which, in turn, may lead to cardiac remodeling in overweight/obese HFpEF.

Keywords:  Circulating CD4+ T lymphocytes; DNA methylation; Diagnostic biomarkers; HFpEF; Liquid biopsy; Network analysis

DOI:  https://doi.org/10.1007/s00395-024-01093-7
iScience. 2024 Dec 20. 27(12): 111467

SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.

Ritam Naha, Rebecca Strohm, Yulia Schaumkessel, Jennifer Urbach, Ilka Wittig, Andreas S Reichert, Arun Kumar Kondadi, Ruchika Anand.

  The MICOS complex, essential for cristae organization, comprises MIC10 and MIC60 subcomplexes, with MIC13 as a crucial subunit. MIC13 mutations cause severe mitochondrial hepato-encephalopathy, cristae defects, and MIC10-subcomplex loss. We demonstrate that depletion of the mitochondrial protease YME1L in MIC13 KO stabilizes MIC10-subcomplex, restoring MIC60-MIC10 interaction and crista junction (CJ) defects, indicating MIC13 is crucial for MIC10-subcomplex stabilization rather than MIC60-MIC10 bridging. We identified stomatin-like protein 2 (SLP2) as a key MIC13 interaction partner, essential for cristae morphology and CJ formation. SLP2 serves as an interaction hub for MICOS subunits and stabilizes MIC26 by protecting it from YME1L-mediated degradation. Deleting both SLP2 and MIC13 impairs MIC60-subcomplex assembly and its nanoscale organization. Restoring the MIC10-subcomplex in MIC13-SLP2 double KO cells through YME1L depletion reinstates MIC60-subcomplex assembly and cristae morphology. Overall, we propose SLP2 and the MIC10-subcomplex act as a proteolytically controlled 'seeder' complex, facilitating MICOS-MIB complex assembly and maintaining mitochondrial integrity.

Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.111467