bims-mimcad 2024-03-31 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–03–31
eight papers selected by
Henver Brunetta, University of Guelph

Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance.
Cardiac Mitochondrial Metabolism During Pregnancy and the Postpartum Period.
HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.
Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.
Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny.
Mitochondrial respiration in peripheral arterial disease depends on stage severity.
Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults with Diabetes.
Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.

Mol Metab. 2024 Mar 23. pii: S2212-8778(24)00052-8. [Epub ahead of print] 101921

Salubrinal promotes phospho-eIF2α-dependent activation of UPR leading to autophagy-mediated attenuation of iron-induced insulin resistance.

Khang Nguyen, Jialing Tang, Sungji Cho, Fan Ying, Hye Kyoung Sung, Kostas Pantopoulos, Gary Sweeney.

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, we first used a cellular model of skeletal muscle cell iron overload and found endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear FoxO localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2α phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative Atg5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. We translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance where administration of salubrinal as pretreatment promoted eIF2α phosphorylation, enhanced autophagic flux in skeletal muscle and improved insulin responsiveness. Together, our results show that salubrinal elicited an eIF2α-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice.

DOI: https://doi.org/10.1016/j.molmet.2024.101921
Am J Physiol Heart Circ Physiol. 2024 Mar 29.

Cardiac Mitochondrial Metabolism During Pregnancy and the Postpartum Period.

Emily B Schulman-Geltzer, Kyle L Fulghum, Richa A Singhal, Bradford G Hill, Helen E Collins.

  The goal of the present study was to characterize changes in mitochondrial respiration in the maternal heart during pregnancy and after birth. Timed pregnancy studies were performed in 12-week-old female FVB/NJ mice, and cardiac mitochondria were isolated from the following groups of mice: non-pregnant (NP), mid-pregnancy (MP), late-pregnancy (LP), and 1-week post-birth (PB). Similar to our previous studies, we observed increased heart size during all stages of pregnancy (e.g., MP and LP) and post-birth (e.g., PB) compared with NP mice. Differential cardiac gene and protein expression analyses revealed changes in several mitochondrial transcripts at LP and PB, including several mitochondrial complex subunits and members of the Slc family, important for mitochondrial substrate transport. Respirometry revealed that pyruvate- and glutamate-supported state 3 respiration was significantly higher in PB versus LP mitochondria, with respiratory control ratio (RCR) values higher in PB mitochondria. In addition, we found that PB mitochondria respired more avidly when given 3-hydroxybutyrate (3-OHB) than mitochondria from NP, MP, and LP hearts, with no differences in RCR. These increases in respiration in PB hearts occurred independent of changes in mitochondrial yield, but were associated with higher abundance of 3-hydroxybutyrate dehydrogenase 1. Collectively, these findings suggest that, after birth, maternal cardiac mitochondria have an increased capacity to use 3-OHB, pyruvate, and glutamate as energy sources; however, increases in mitochondrial efficiency in the postpartum heart appear limited to carbohydrate and amino acid metabolism.

Keywords:  3-hydroxybutyrate; female cardiac biology; mitochondrial subunit complexes; physiological hypertrophy; solute transporters

DOI:  https://doi.org/10.1152/ajpheart.00127.2024
J Cell Mol Med. 2024 Apr;28(8): e18276

HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Nan Zhang, Zi-Ying Zhou, Yan-Yan Meng, Hai-Han Liao, Shan-Qi Mou, Zheng Lin, Han Yan, Si Chen, Qi-Zhu Tang.

  Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Keywords:  HINT2; NDUFs; cardiac remodelling; hypertrophy; mitochondrial complex I

DOI:  https://doi.org/10.1111/jcmm.18276
Circulation. 2024 Mar 27.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

Kristoffer Berg-Hansen, Nigopan Gopalasingam, Kristian Hylleberg Christensen, Bertil Ladefoged, Mads Jønsson Andersen, Steen Hvitfeldt Poulsen, Barry A Borlaug, Roni Nielsen, Niels Møller, Henrik Wiggers.

   BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.
METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.
RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes.
CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Keywords:  cardiac output; esters; exercise; heart failure; hemodynamics; hydroxybutyrate dehydrogenase; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067971
J Nutr Biochem. 2024 Mar 21. pii: S0955-2863(24)00058-5. [Epub ahead of print] 109625

Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny.

Brenda A Nagagata, Gabrielle Brito, Fernanda Ornellas, Carlos A Mandarim-de-Lacerda, Marcia Barbosa Aguila.

  Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17 % kJ as fat) or a high-fat diet (HF, 49 % kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n=10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, Principal Component Analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.

Keywords:  Mel; fetal programming; hypothalamus; maternal obesity; thermogenesis

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109625
J Cell Mol Med. 2024 Apr;28(8): e18126

Mitochondrial respiration in peripheral arterial disease depends on stage severity.

Fiona Speichinger, Alexandra Gratl, Ben Raude, Larissa Schawe, Jan Carstens, Nina A Hering, Andreas Greiner, Dominik Pesta, Jan Paul Frese.

  Peripheral arterial disease (PAD) is an increasing cause of morbidity and its severity is graded based on clinical manifestation. To investigate the influence of the different stages on myopathy of ischemic muscle we analysed severity-dependent effects of mitochondrial respiration in PAD. Eighteen patients with severe PAD, defined as chronic limb-threatening ischemia, 47 patients with intermittent claudication (IC) and 22 non-ischemic controls were analysed. High-resolution respirometry (HRR) was performed on muscle biopsies of gastrocnemius and vastus lateralis muscle of patients in different PAD stages to investigate different respiratory states. Results from HRR are given as median and interquartile range and were normalized to citrate synthase activity (CSA), a marker for mitochondrial content. In order to account for inter-individual differences between patients and controls, we calculated the ratio of O₂-flux in gastrocnemius muscle over vastus muscle ('GV ratio'). CSA of the gastrocnemius muscle as a proxy for mitochondrial content was significantly lower in critical ischemia compared to controls. Mitochondrial respiration normalized to CSA was higher in IC compared to controls. Likewise, the GV ratio was significantly higher in IC compared to control. Mitochondrial respiration and CSA of PAD patients showed stage-dependent modifications with greater changes in the mild PAD stage group (IC).

Keywords:  PAD; chronic limb‐threatening ischemia; intermittent claudication; mitochondrial function; mitochondrial respiration; myopathy; peripheral arterial disease

DOI:  https://doi.org/10.1111/jcmm.18126
Diabetes. 2024 Mar 29. pii: db230827. [Epub ahead of print]

Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults with Diabetes.

Sofhia V Ramos, Giovanna Distefano, Li-Yung Lui, Peggy M Cawthon, Philip Kramer, Ian J Sipula, Fiona M Bello, Theresa Mau, Michael J Jurczak, Anthony J Molina, Erin E Kershaw, David J Marcinek, Eric Shankland, Frederico G S Toledo, Anne B Newman, Russell T Hepple, Stephen B Kritchevsky, Bret H Goodpaster, Steven R Cummings, Paul M Coen.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial oxidative capacity on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes as well as determine their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n=159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles when compared to those without diabetes (n=717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walk speed between older adults with and without diabetes. Additional adjustments with BMI and co-morbidities further explained the group differences in walk speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

DOI: https://doi.org/10.2337/db23-0827
Science. 2024 Mar 29. 383(6690): 1484-1492

Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.

Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.

Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.

DOI: https://doi.org/10.1126/science.adh2771