bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–12–22
seven papers selected by
Henver Brunetta, Karolinska Institutet



  1. J Clin Invest. 2024 Dec 16. pii: e176708. [Epub ahead of print]134(24):
      Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
    Keywords:  Cardiology; Glucose metabolism; Intermediary metabolism; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI176708
  2. Circulation. 2024 Dec 14.
       BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major health concern. Pathological stimuli and interactions between cardiac fibroblasts (CFs) and other cell types may lead to cardiac fibrosis and diastolic dysfunction, which are hallmarks of HFpEF. Interstitial and perivascular cardiac fibrosis correlates with poor prognosis in HFpEF; however, mechanisms of fibrosis remain poorly elucidated, and targeted therapies are lacking. Cardiac reprogramming is a promising therapeutic approach for myocardial infarction that facilitates cardiac regeneration and antifibrosis action through Mef2c/Gata4/Tbx5/Hand2 (MGTH) overexpression in resident CFs. However, the efficacy of this approach on HFpEF is yet to be established.
    METHODS: Herein, we examined the effects of cardiac reprogramming in HFpEF using Tcf21iCre/Tomato/MGTH2A transgenic mice, which expressed both MGTH and reporter expression in CFs for cardiac reprogramming and lineage tracing upon tamoxifen administration. To establish HFpEF model mice, we used a combination of a high-fat diet and nitric oxide synthase inhibition. Bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics were conducted to determine fibrotic mechanisms and the efficacy of cardiac reprogramming in HFpEF. We generated new tamoxifen-inducible transgenic mice overexpressing each reprogramming factor in CFs to investigate the effect of single factors. Last, we analyzed the effect of reprogramming factors in human CFs.
    RESULTS: Cardiac reprogramming with MGTH overexpression improved diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss in HFpEF. Cardiac reprogramming converted approximately 1% of resident CFs into induced cardiomyocytes. Bulk RNA-seq indicated that MGTH overexpression upregulated genes related to heart contraction and suppressed the fetal gene program (Nppa and Nppb) and proinflammatory and fibrotic signatures. Single-cell RNA-sequencing and spatial transcriptomics revealed that multiple CF clusters upregulated fibrotic genes to induce diffuse interstitial fibrosis, whereas distinct CF clusters generated focal perivascular fibrosis in HFpEF. MGTH overexpression reversed these profibrotic changes. Among 4 reprogramming factors, only Gata4 overexpression in CFs reduced fibrosis and improved diastolic dysfunction in HFpEF by suppressing CF activation without generating new induced cardiomyocytes. Gata4 overexpression also suppressed profibrotic signatures in human CFs.
    CONCLUSIONS: Overexpressing Gata4 in CFs may be a promising therapeutic approach for HFpEF by suppressing fibrosis and improving diastolic dysfunction.
    Keywords:  cardiac fibroblasts; fibrosis; heart failure; single-cell RNA-sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067504
  3. Mol Metab. 2024 Dec 13. pii: S2212-8778(24)00213-8. [Epub ahead of print] 102082
      In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1-XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.
    Keywords:  Chromatin remodeling; Creatine pathway; Glycolysis; Immunometabolism; Tunicamycin
    DOI:  https://doi.org/10.1016/j.molmet.2024.102082
  4. Cardiovasc Diabetol. 2024 Dec 18. 23(1): 447
       BACKGROUND: Epicardial adipose tissue (EAT) has been suggested to play paradoxical roles in patients with heart failure. The role of EAT in dilated cardiomyopathy (DCM) patients remains unclear. We aimed to assess the associations between the dynamic changes EAT and left ventricular reverse remodeling (LVRR) in DCM patients based on baseline and follow-up CMR.
    METHODS: In this prospective study, we consecutive enrolled DCM patients with baseline and follow-up cardiac magnetic resonance (CMR) examinations. All participating patients underwent 1-2 years of guideline-directed medical therapy (GDMT) at follow-up. The EAT was measured as pericardial and epicardial fat thickness, and paracardial fat volume, while the abdominal adiposity was measured in terms of subcutaneous and visceral fat thickness. The univariable and multivariable logistic regression analyses were performed to evaluate the associations of changes in abdominal and epicardial adiposities with the presence of LVRR.
    RESULTS: A total of 232 patients (mean age, 45.7 ± 15.1 years, 157 male) at baseline were enrolled. After a period of GDMT with a median duration of 15.5 months (interquartile range, 12.5-19.1 months) all participants underwent follow-up CMR with the same standardized protocol. Patients who reached LVRR showed a significant increment in EAT parameters compared to those who did not. After adjusting for age, sex, and delta changes of body mass index (BMI), the increment of pericardial fat thickness (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.27 to 1.83; p < 0.001), epicardial fat thickness (OR: 2.10; 95% CI: 1.68 to 2.63; p < 0.001), and paracardial fat volume (OR: 1.01; 95% CI: 1.01 to 1.02; p = 0.001) were significantly associated with LVRR.
    CONCLUSIONS: In DCM patients, the CMR-derived EAT parameters increased after 1-2 years of GDMT and significantly correlated with improved ventricular structure and function, independent of changes in BMI and abdominal adiposity, which may indicate the potential protective role of EAT in DCM patients.
    TRIAL REGISTRATION: URL: https://www.
    CLINICALTRIALS: gov ; Unique identifier: ChiCTR1800017058.
    Keywords:  Cardiac adipose tissue; Dilated cardiomyopathy; Guideline-directed medical therapy; Reverse remodeling
    DOI:  https://doi.org/10.1186/s12933-024-02517-3
  5. JAMA Cardiol. 2024 Dec 18.
       Importance: Nitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration.
    Objective: To assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF.
    Design, Setting, and Participants: This multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024.
    Intervention: Potassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between.
    MAIN OUTCOMES AND MEASURES: The coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire.
    Results: Eighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P < .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated.
    Conclusions and Relevance: In this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF.
    Trial Registration: ClinicalTrials.gov Identifier: NCT02840799.
    DOI:  https://doi.org/10.1001/jamacardio.2024.4417
  6. Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00447-9. [Epub ahead of print]
      Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.
    Keywords:  FcRn; IgG; adipose tissue remodeling; insulin receptor; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.001
  7. Circulation. 2024 Dec 17.
       BACKGROUND: Mitochondrial dysfunction is a key factor in the development of atherogenesis. METTL4 (methyltransferase-like protein 4) mediates N6- methyldeoxyadenosine (6mA) of mammalian mitochondrial DNA (mtDNA). However, the role of METTL4-mediated mitoepigenetic regulation in atherosclerosis is still unknown. This study aims to investigate the potential involvement of METTL4 in atherosclerosis, explore the underlying mechanism, and develop targeted strategies for treating atherosclerosis.
    METHODS: Expression levels of mtDNA 6mA and METTL4 were determined in atherosclerotic lesions. We explored the mechanism of METTL4 involvement in atherosclerosis using Mettl4Mac-KO-Apoe-/- and Mettl4MUT-Apoe-/- mice and cell models, as well as bone marrow transplantation. Natural compound libraries were screened to identify potent METTL4 antagonists. In addition, bioinspired proteolysis targeting chimera technology targeting macrophages within plaques was used to increase the efficacy of the METTL4 antagonist.
    RESULTS: The expression levels of mtDNA 6mA and METTL4 were significantly increased in plaque macrophages. Mettl4Mac-KO-Apoe-/- mice displayed suppressed mtDNA 6mA levels and atherosclerotic progression, which were reversed by METTL4 restoration through bone marrow transplantation (n=6). Mechanistically, elevated METTL4 expression reduces MT-ATP6 expression by suppressing its transcription, thereby impairing the activity of mitochondrial respiration chain complex V. This disruption leads to the accumulation of excess protons in the mitochondrial intermembrane space, causing mitochondrial dysfunction. Consequently, mtDNA is released into the cytoplasm, ultimately triggering inflammasome activation. All results were reversed by the mutation in the METTL4 methyltransferase active site. Mettl4MUT-Apoe-/- mice showed suppressed mtDNA 6mA levels and atherosclerotic progression and repaired mitochondrial function of macrophage, which were reversed by METTL4 restoration through bone marrow transplantation (n=6). Pemetrexed was identified as the first METTL4 antagonist to effectively alleviate atherosclerotic progression. Furthermore, we generated a proteolysis targeting chimera drug based on pemetrexed that specifically targeted METTL4 in macrophages within plaques, showing a promising therapeutic effect on atherosclerosis.
    CONCLUSIONS: This study revealed a novel mechanism by which mtDNA 6mA orchestrated mitochondrial function-related gene expression in macrophages, thereby promoting atherosclerosis. Through various experimental techniques, such as gene manipulation, pharmacological inhibition, and proteolysis targeting chimera, this study demonstrated that mtDNA 6mA and its specific enzyme METTL4 hold potential as therapeutic targets for atherosclerosis.
    Keywords:  METTL4; atherosclerosis; macrophage; mitochondria; mtDNA 6mA
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.069574