bims-mimcad 2024-08-11 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–08–11
ten papers selected by
Henver Brunetta, University of Guelph

SLC25A48 controls mitochondrial choline import and metabolism.
Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.
NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress.
Mitochondrial fragmentation in early differentiation of human MB135 myoblasts: Role of mitochondrial ROS production in the absence of depolarization.
Harmonization of experimental procedures to assess mitochondrial respiration in human permeabilized skeletal muscle fibers.
Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.
Purinosomes spatially co-localize with mitochondrial transporters.
Peroxiredoxin 2 Regulates DAF-16/FOXO Mediated Mitochondrial Remodelling in Response to Exercise that is Disrupted in Ageing.
Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00281-X. [Epub ahead of print]

SLC25A48 controls mitochondrial choline import and metabolism.

Anthony R P Verkerke, Xu Shi, Mark Li, Yusuke Higuchi, Tadashi Yamamuro, Daisuke Katoh, Hiroshi Nishida, Christopher Auger, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.

  Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.

Keywords:  bioenergetics; brown adipose tissue; cancer metabolism; choline; mitochondria; purine nucleotides

DOI:  https://doi.org/10.1016/j.cmet.2024.07.010
Eur J Heart Fail. 2024 Aug 09.

Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.

Navid Koleini, Mariam Meddeb, Liang Zhao, Mohammad Keykhaei, Seoyoung Kwon, Farnaz Farshidfar, Virginia S Hahn, Erika L Pearce, Kavita Sharma, David A Kass.

   AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown.
METHODS AND RESULTS: Endomyocardial biopsies from HFpEF (n = 37) and non-failing controls (n = 21) were assayed by non-targeted or targeted metabolomics and immunoblot to determine glycolytic and ancillary pathway metabolites and protein expression of their regulating enzymes. Glucose and GLUT1 expression were higher in HFpEF, but prominent glycolytic metabolites: glucose-6-phosphate, fructose-1,6-biphosphate (F1,6bP), and 3-phosphoglycerate were reduced by -78%, -91%, and -73%, respectively, versus controls. Expression of their corresponding synthesizing enzymes hexokinase, phospho-fructokinase, and phosphoglycerate kinase were also significantly lower (all p < 0.0005). Pentose phosphate and hexosamine biosynthetic pathway metabolites were reduced while glycogen content increased. Despite proximal reduction in key glycolytic intermediates, pyruvate increased but mitochondrial pyruvate transporter (MPC1) expression was reduced. Pyruvate dehydrogenase converting pyruvate to acetyl-CoA was more activated but some Krebs cycle intermediates were reduced. This HFpEF glycolytic profile persisted after adjusting for body mass index (BMI), diabetes, age, and sex, or in subgroup analysis with controls and HFpEF matched for BMI and diabetes/insulin history. In HFpEF, BMI but not glycated haemoglobin negatively correlated with F1,6bP (p = 7e-5, r = -0.61) and phosphoenolpyruvate (p = 0.006, r = -0.46).
CONCLUSIONS: Human HFpEF myocardium exhibits reduced glycolytic and ancillary pathway intermediates and expression of their synthesizing proteins. This combines features reported in HF with reduced ejection fraction and obesity/diabetes that likely exacerbate metabolic inflexibility.

Keywords:  Glycolysis; HFpEF; Heart failure; Human; Metabolomics; Myocardium

DOI:  https://doi.org/10.1002/ejhf.3389
EBioMedicine. 2024 Aug 03. pii: S2352-3964(24)00304-9. [Epub ahead of print]106 105268

NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress.

Hong Peng, Jiali Yuan, Zhengshuai Wang, Binfeng Mo, Yihui Wang, Yuepeng Wang, Qunshan Wang.

   BACKGROUND: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive.
METHODS: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms.
FINDINGS: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes.
INTERPRETATION: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM.
FUNDING: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

Keywords:  Atrial cardiomyopathy; Atrial fibrillation; Energy metabolism; Mitochondria; NR4A3; Oxidative stress

DOI:  https://doi.org/10.1016/j.ebiom.2024.105268
Life Sci. 2024 Aug 02. pii: S0024-3205(24)00531-9. [Epub ahead of print]354 122941

Mitochondrial fragmentation in early differentiation of human MB135 myoblasts: Role of mitochondrial ROS production in the absence of depolarization.

Daniil A Chernyavskij, Konstantin G Lyamzaev, Olga Yu Pletjushkina, Fei Chen, Anna Karpukhina, Yegor S Vassetzky, Boris V Chernyak, Ekaterina N Popova.

   AIMS: Study of the role of mitochondria-generated reactive oxygen species (mtROS) and mitochondrial polarization in mitochondrial fragmentation at the initial stages of myogenesis.
MAIN METHODS: Mitochondrial morphology, Drp1 protein phosphorylation, mitochondrial electron transport chain components content, mtROS and mitochondrial lipid peroxidation levels, and mitochondrial polarization were evaluated on days 1 and 2 of human MB135 myoblasts differentiation. A mitochondria-targeted antioxidant SkQ1 was used to elucidate the effect of mtROS on mitochondria.
KEY FINDINGS: In immortalized human MB135 myoblasts, mitochondrial fragmentation began on day 1 of differentiation before the myoblast fusion. This fragmentation was preceded by dephosphorylation of p-Drp1 (Ser-637). On day 2, an increase in the content of some mitochondrial proteins was observed, indicating mitochondrial biogenesis stimulation. Furthermore, we found that myogenic differentiation, even on day 1, was accompanied both by an increased production of mtROS, and lipid peroxidation of the inner mitochondrial membrane. SkQ1 blocked these effects and partially reduced the level of mitochondrial fragmentation, but did not affect the dephosphorylation of p-Drp1 (Ser-637). Importantly, mitochondrial fragmentation at early stages of MB135 differentiation was not accompanied by depolarization, as an important stimulus for mitochondrial fragmentation.
SIGNIFICANCE: Mitochondrial fragmentation during early myogenic differentiation depends on mtROS production rather than mitochondrial depolarization. SkQ1 only partially inhibited mitochondrial fragmentation, without significant effects on mitophagy or early myogenic differentiation.

Keywords:  Mitochondrial fragmentation; Mitochondrial membrane potential (ΔΨm); Mitochondrial reactive oxygen species (mtROS); Myogenesis; Myogenic differentiation

DOI:  https://doi.org/10.1016/j.lfs.2024.122941
Free Radic Biol Med. 2024 Aug 01. pii: S0891-5849(24)00585-9. [Epub ahead of print]

Harmonization of experimental procedures to assess mitochondrial respiration in human permeabilized skeletal muscle fibers.

Carolina Doerrier, Pau Gama-Perez, Dominik Pesta, Giovanna Distefano, Stine D Soendergaard, Karoline Maise Chroeis, Alba Gonzalez-Franquesa, Bret H Goodpaster, Clara Prats, Marta Sales-Pardo, Roger Guimera, Paul M Coen, Erich Gnaiger, Steen Larsen, Pablo M Garcia-Roves.

   AIM: High-resolution respirometry in human permeabilized muscle fibers is extensively used for analysis of mitochondrial adaptions to nutrition and exercise interventions, and is linked to athletic performance. However, the lack of standardization of experimental conditions limits quantitative inter- and intra-laboratory comparisons.
METHODS: In our study, an international team of investigators measured mitochondrial respiration of permeabilized muscle fibers obtained from three biopsies (vastus lateralis) from the same healthy volunteer to avoid inter-individual variability. High-resolution respirometry assays were performed together at the same laboratory to assess whether the heterogenity in published results are due to the effects of respiration media (MiR05 versus Z) with or without the myosin inhibitor blebbistatin at low- and high-oxygen regimes.
RESULTS: Our findings reveal significant differences between respiration media for OXPHOS and ET capacities supported by NADH&succinate-linked substrates at different oxygen concentrations. Respiratory capacities were approximately 1.5-fold higher in MiR05 at high-oxygen regimes compared to medium Z near air saturation. The presence or absence of blebbistatin in human permeabilized muscle fiber preparations was without effect on oxygen flux.
CONCLUSION: Our study constitutes a basis to harmonize and establish optimum experimental conditions for respirometric studies of permeabilized human skeletal muscle fibers to improve reproducibility.

Keywords:  O(2) regime; blebbistatin; high-resolution respirometry; mitochondrial respiration; permeabilized skeletal muscle fibers; respiration medium MiR05; respiration medium Z

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.07.039
Circulation. 2024 Aug 05.

Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.

Atsushi Tada, Daniel Burkhoff, Jwan A Naser, Tomonari Harada, Bianca Pourmussa, Yogesh N V Reddy, Michael D Jensen, Rickey Carter, Ryan T Demmer, Jeffrey Testani, Julio A Chirinos, Barry A Borlaug.

   BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF.
METHODS: In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model.
RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001).
CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Keywords:  Dapagliflozin; HFpEF; arterial compliance; arterial stiffness; exercise; heart failure; hemodynamics; mechanism; vascular stiffness; venous function

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.068788
J Biol Chem. 2024 Aug 02. pii: S0021-9258(24)02121-5. [Epub ahead of print] 107620

Purinosomes spatially co-localize with mitochondrial transporters.

Zhou Sha, Stephen J Benkovic.

  In this study, we advance our understanding of the spatial relationship between the purinosome, a liquid condensate consisting of six enzymes involved in de novo purine biosynthesis, and mitochondria. Previous research has shown that purinosomes move along tubulin toward mitochondria, suggesting a direct uptake of glycine from mitochondria. Here, we propose that the purinosome is located proximally to the mitochondrial transporters SLC25A13 and SLC25A38, facilitating the uptake of glycine, aspartate, and glutamate, essential factors for purine synthesis. We utilized the proximity ligation assay (PLA) and APEX proximity labeling to investigate the association between purinosome proteins and mitochondrial transporters. Our results indicate that purinosome assembly occurs close to the mitochondrial membrane under purine-deficient conditions, with the transporters migrating to be adjacent to the purinosome. Furthermore, both targeted and non-targeted analyses suggest that the SLC25A13-APEX2-V5 probe accurately reflects endogenous cellular status. These findings provide insights into the spatial organization of purine biosynthesis and lay the groundwork for further investigations into additional proteins involved in this pathway.

Keywords:  APEX; Purinosomes; de novo purine biosynthesis; mitochondrial transporter; proximity ligation assay (PLA)

DOI:  https://doi.org/10.1016/j.jbc.2024.107620
Mol Metab. 2024 Aug 06. pii: S2212-8778(24)00134-0. [Epub ahead of print] 102003

Peroxiredoxin 2 Regulates DAF-16/FOXO Mediated Mitochondrial Remodelling in Response to Exercise that is Disrupted in Ageing.

Qin Xia, Penglin Li, José C Casas-Martinez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Katarzyna Goljanek-Whysall, Brian McDonagh.

  Ageing is associated with mitochondrial dysfunction and increased oxidative stress. Exercise generates endogenous reactive oxygen species (ROS) and promotes rapid mitochondrial remodelling. We investigated the role of Peroxiredoxin 2 (PRDX-2) in mitochondrial adaptations to exercise and ageing using Caenorhabditis elegans as a model system. PRDX-2 was required for the mitochondrial remodelling in response to exercise mediated by DAF-16 transcription factor activation and regulation of mitochondrial fusion gene eat-3. Employing an acute exercise and recovery cycle, we demonstrated exercise-induced mitochondrial ER contact sites (MERCS) assembly and mitochondrial remodelling dependent on PRDX-2 and DAF-16 signalling. There was increased mitochondrial fragmentation, elevated ROS and an altered redox state of PRDX-2 concomitant with impaired DAF-16 nuclear localisation during ageing. Similarly, the prdx-2 mutant strain exhibited increased mitochondrial fragmentation and a failure to activate DAF-16 required for mitochondrial fusion. Collectively, our data highlight the critical role of PRDX-2 in orchestrating mitochondrial remodelling in response to a physiological stress by regulating DAF-16 nuclear localisation.

Keywords:  Ageing; C. elegans; DAF-16; Exercise; Mitochondrial ER Contact Sites; Peroxiredoxin 2

DOI:  https://doi.org/10.1016/j.molmet.2024.102003
Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]

Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.

  Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
J Endocrinol. 2024 Aug 01. pii: JOE-23-0350. [Epub ahead of print]

Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Cheng-Hsuan Tsai, Zheng-Wei Chen, Bo-Ching Lee, Che-Wei Liao, Yi-Yao Chang, Yan-Rou Tsai, Chia-Hung Chou, Vin-Cent Wu, Chi-Sheng Hung, Yen-Hung Lin.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific protein, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

DOI: https://doi.org/10.1530/JOE-23-0350