bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–11–10
43 papers selected by
Henver Brunetta, Karolinska Institutet
  1. Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.
  2. Cardiac overexpression of a mitochondrial SUR2A splice variant impairs cardiac function and worsens myocardial ischemia reperfusion injury in female mice.
  3. Effects of Obesity and Hyperglycemia on Postprandial Insulin-Mediated and Non-Insulin-Mediated Glucose Disposal.
  4. Glucagon-like Peptide-1 Receptor Agonists in the Context of Pathophysiology of Diverse Heart Failure with Preserved Ejection Fraction Phenotypes: Potential Benefits and Mechanisms of Action.
  5. Adipose Tissue Insulin Resistance in Children and Adolescents: Linking Glucose and Free Fatty Acid Metabolism to Hepatic Injury Markers.
  6. AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling.
  7. PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway.
  8. Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
  9. Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction.
  10. HADHA Regulates Respiratory Complex Assembly and Couples FAO and OXPHOS.
  11. Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility.
  12. Prevalence of Subclinical Hypothyroidism in a Non-Diabetic Young Female Population and Its Impact on Diabetes and Cardiometabolic Risk.
  13. GDF15 is required for maintaining subcutaneous adipose tissue lipid metabolic signature.
  14. A multiorgan map of metabolic, signaling, and inflammatory pathways that coordinately control fasting glycemia in mice.
  15. Sestrin2 Attenuates Myocardial Endoplasmic Reticulum Stress and Cardiac Dysfunction During Ischemia/Reperfusion Injury.
  16. Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.
  17. In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human visceral fat.
  18. Treatment Patterns and Glycaemic Control Between 2015 and 2019 in Tianjin, China: A Real-World Study of Adults with Type 2 Diabetes.
  19. Unveiling the Role of Magnesium: Insights into Insulin Resistance and Glycemic Control in Type 2 Diabetes.
  20. Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial.
  21. Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.
  22. Mitochondrial respiratory capacity is not altered in aging rat brains with or without memory impairment.
  23. Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.
  24. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  25. Effects of ipragliflozin on skeletal muscle adiposity in patients with diabetes and metabolic dysfunction-associated steatotic liver disease.
  26. Analysis of mitochondrial protein aggregation and disaggregation.
  27. GLIS3: a novel transcriptional regulator of mitochondrial functions and metabolic reprogramming in postnatal kidney and polycystic kidney disease.
  28. Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.
  29. Coronary arteriovenous fistula originating from the left coronary artery and draining into the superior vena cava.
  30. REGγ deficiency ameliorates hepatic ischemia and reperfusion injury in a mitochondrial p66shc dependent manner in mice.
  31. Mitochondrial respiratory complex II is altered in renal carcinoma.
  32. CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
  33. Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy.
  34. Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes: A systematic review with multiple network meta-regressions.
  35. Mitochondrial nucleoids.
  36. Analysis of mitochondrial biogenesis regulation by oxidative stress.
  37. Monitoring retro-translocation of proteins from the mitochondrial intermembrane space.
  38. Resveratrol relieves myocardial ischemia-reperfusion injury through inhibiting AKT nitration modification.
  39. Mitochondrial quality control measures, systemic inflammation, and lower-limb muscle power in older adults: a PROMPT secondary analysis.
  40. Machine learning-based clustering identifies obesity subgroups with differential multi-omics profiles and metabolic patterns.
  41. Heart Failure With Preserved Ejection Fraction-A Role for Invasive Hemodynamics.
  42. Monitoring α-helical membrane protein insertion into the outer mitochondrial membrane of yeast cells.
  43. Proteinuria, Blinded by Bright Light.
  1. Acta Physiol (Oxf). 2024 Nov 01. e14249
    Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.
    Michael W Schleh, Benjamin J Ryan, Cheehoon Ahn, Alison C Ludzki, Douglas W Van Pelt, Lisa M Pitchford, Olivia K Chugh, Austin T Luker, Kathryn E Luker, Dmitri Samovski, Nada A Abumrad, Charles F Burant, Jeffrey F Horowitz.
       AIM: To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake.
    METHODS: Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic-euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]).
    RESULTS: Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW.
    CONCLUSION: Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.
    Keywords:  CD36; insulin resistance; lipid droplet; obesity; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.14249
  2. J Mol Cell Cardiol Plus. 2024 Sep;9
    Cardiac overexpression of a mitochondrial SUR2A splice variant impairs cardiac function and worsens myocardial ischemia reperfusion injury in female mice.
    Allison C Wexler, Holly Dooge, Sarah El-Meanawy, Elizabeth Santos, Timothy Hacker, Aditya Tewari, Francisco J Alvarado, Mohun Ramratnam.
      The small splice variant of the sulfonylurea receptor protein isoform 2 A (SUR2A-55) targets mitochondria and enhances mitoKATP activity. In male mice the overexpression of this protein promotes cardioprotection, reducing myocardial injury after an ischemic insult. However, it is unclear what impact SUR2A-55 overexpression has on the female myocardium. To investigate the impact of SU2R2A-55 on the female heart, mice with cardiac specific transgenic overexpression of SUR2A-55 (TGSUR2A-55) were examined by resting echocardiography and histopathology. In addition, hearts were subjected to ischemia reperfusion (IR) injury. Female TGSUR2A-55 mice had resting LV dysfunction and worse hemodynamic recovery with increased infarct size after IR injury. RNA-seq analysis found 227 differential expressed genes between WT and TGSUR2A-55 female mouse hearts that were enriched in pathways of cellular metabolism. This was in direct contrast to male mice that had only four differentially expressed genes. Female TGSUR2A-55 mice compared to female WT mice had reduced cardiomyocyte mitochondrial membrane potential without a change in electron transport chain protein expression. In addition, isolated mitochondria from female TGSUR2A-55 hearts displayed reduced sensitivity to ATP and diazoxide suggestive of increased mitoKATP activity. In conclusion, our data suggests that female TGSUR2A-55 mice are unable to tolerate a more active mitoKATP channel leading to LV dysfunction and worse response to IR injury. This is in direct contrast to our prior report showing cardioprotection in male mice overexpressing SUR2A-55 in heart. Future research directed at examining the expression and activity of mitoKATP subunits according to sex may elucidate different treatments for male and female patients.
    Keywords:  ATP sensitive potassium channels; Cardiac metabolism; Myocardial ischemia reperfusion injury; Sex differences; Sulfonylurea receptors
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100088
  3. Diabetes Care. 2024 Nov 05. pii: dc241280. [Epub ahead of print]
    Effects of Obesity and Hyperglycemia on Postprandial Insulin-Mediated and Non-Insulin-Mediated Glucose Disposal.
    Bettina Mittendorfer, Bruce W Patterson, Gordon I Smith, Mihoko Yoshino, Samuel Klein.
       OBJECTIVE: To evaluate total, insulin-mediated, and non-insulin-mediated glucose disposal (TGD, IMGD, and NIMGD) after ingesting glucose in people with obesity and different glycemic status.
    RESEARCH DESIGN AND METHODS: We developed and validated a new glucose tracer model in conjunction with an oral glucose tolerance test to determine IMGD, NIMGD, and TGD (sum of IMGD and NIMGD) after glucose ingestion in four groups of people: 1) lean with normal glucose tolerance (NGT), 2) obese with insulin resistance and NGT due to hyperinsulinemia (Ob-NGT group), 3) obese with insulin resistance and impaired glucose tolerance (IGT) due to inadequate hyperinsulinemia (Ob-IGT group), and 4) obese with insulin resistance and type 2 diabetes due to marked insulin insufficiency (Ob-T2D group). In addition, we evaluated the effect of intensive lifestyle therapy (ILT) that caused ∼15% weight loss on IMGD and NIMGD in people with obesity and type 2 diabetes (T2D).
    RESULTS: IMGD progressively decreased and NIMGD progressively increased from lean to Ob-NGT to Ob-IGT to Ob-T2D. IMGD accounted for about 70%, 65%, 50%, and 20% of TGD, and NIMGD accounted for ∼40%, 35%, 50%, and 80% of TGD in lean, Ob-NGT, Ob-IGT and Ob-T2D, respectively. Although NIMGD was approximately twofold and approximately threefold higher in Ob-IGT and Ob-T2D compared with Ob-NGT, NIMGD only partially compensated for markedly impaired IMGD in the Ob-IGT and Ob-T2D. ILT in people with obesity and T2D increased IMGD and decreased NIMGD.
    CONCLUSIONS: NIMGD is a major mechanism of postprandial TGD in people with insulin resistance and inadequate insulin secretion.
    DOI:  https://doi.org/10.2337/dc24-1280
  4. Card Fail Rev. 2024 ;10 e14
    Glucagon-like Peptide-1 Receptor Agonists in the Context of Pathophysiology of Diverse Heart Failure with Preserved Ejection Fraction Phenotypes: Potential Benefits and Mechanisms of Action.
    Aleksandra Bykova, Maria Serova, Maria Chashkina, Raisa Kosharnaya, Zukhra Salpagarova, Denis Andreev, Ilya Giverts.
      This review examines the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on different heart failure phenotypes with preserved ejection fraction (HFpEF). Traditional heart failure treatment modalities have shown limited success in improving outcomes for patients with HFpEF, but new evidence suggests that GLP-1RAs could be beneficial. The positive effects of GLP-1RAs are likely due to their ability to reduce systemic inflammation, enhance metabolism and directly affect the cardiovascular system, addressing critical aspects of HFpEF pathology. However, the exact impact of GLP-1RAs on clinical outcomes for different HFpEF phenotypes is still unclear. This review highlights both the potential benefits and the current limitations of GLP-1RA therapy, suggesting a careful approach for their application in clinical practice.
    Keywords:  Glucagon-like peptide-1 receptor agonists; arterial hypertension; atrial fibrillation; coronary artery disease; diabetes; heart failure with preserved ejection fraction; obesity
    DOI:  https://doi.org/10.15420/cfr.2024.06
  5. Am J Physiol Endocrinol Metab. 2024 Nov 06.
    Adipose Tissue Insulin Resistance in Children and Adolescents: Linking Glucose and Free Fatty Acid Metabolism to Hepatic Injury Markers.
    J Bonet, Ram Weiss, Alfonso Galderisi, Chiara Dalla Man, Sonia Caprio, Nicola Santoro.
      Obesity is one of the leading causes of the development of insulin resistance, diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. With the progression of insulin resistance, both glucose and free fatty acid (FFA) plasma levels are elevated, leading to cardiometabolic complications such as impaired glucose tolerance (IGT), type 2 diabetes and liver fat accumulation. Oral minimal models were used to estimate insulin sensitivity indexes (SI and SIFFA) in 375 adolescents with obesity. Differences between NGT and IGT were assessed by using Mann-Whitney test, while the relationship between insulin sensitivities and plasma alanine transaminase (ALT) by using Spearman correlation and linear regression model of the log transformed variables. Also, 48 youth repeated the OGTT and the measurement of liver function test after ~1.3 years of follow-up. Insulin sensitivity indexes resulted to be statistically different in NGT compared to IGT (P<10-6) and correlated to each other (ρ=0.7, P<10-6). Lipolysis was completely suppressed after 30min in NGT, compared to 120min in IGT. SI and SIFFA were both statistically correlated with ALT ρ= -0.19 (P<10-3). Also, the percentages of variation of SIFFA and ALT between the first and second visit correlated significantly (ρ= -0.47, P=0.002). FFA minimal model can be used to estimate adipose tissue lipolysis in youth with obesity. The relationship of SI and SIFFA and with ALT, along with the progression of the impairment of adipose tissue insulin sensitivity, showed a systemic insulin resistance state, underlying the interrelationship of glucose and FFA metabolism and with hepatic damage.
    Keywords:  adolescents; free fatty acids; glucose tolerance; lypolisys
    DOI:  https://doi.org/10.1152/ajpendo.00270.2024
  6. Nat Commun. 2024 Nov 06. 15(1): 9602
    AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling.
    Shu Su, Chao Quan, Qiaoli Chen, Ruizhen Wang, Qian Du, Sangsang Zhu, Min Li, Xinyu Yang, Ping Rong, Jiang Chen, Yingyu Bai, Wen Zheng, Weikuan Feng, Minjun Liu, Bingxian Xie, Kunfu Ouyang, Yun Stone Shi, Feng Lan, Xiuqin Zhang, Ruiping Xiao, Xiongwen Chen, Hong-Yu Wang, Shuai Chen.
      The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca2+) homeostasis, which are two critical assaults leading to cardiac dysfunction. The molecular mechanisms underlying these alterations in obese heart are not well understood. Here, we show that the Rab-GTPase activating protein AS160 is a lipid-responsive regulator of Ca2+ homeostasis through governing lysophosphatidylinositol metabolism and signaling. Palmitic acid/high fat diet inhibits AS160 activity through phosphorylation by NEK6, which consequently activates its downstream target Rab8a. Inactivation of AS160 in cardiomyocytes elevates cytosolic Ca2+ that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca2+ release from sarcoplasmic reticulum. Inactivation of NEK6 prevents inhibition of AS160 by palmitic acid/high fat diet, and alleviates cardiac dysfunction in high fat diet-fed mice. Together, our findings reveal a regulatory mechanism governing metabolic remodeling and Ca2+ homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-024-54031-5
  7. Cardiovasc Res. 2024 Nov 05. pii: cvae238. [Epub ahead of print]
    PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway.
    Haobin Zhou, Xiao Wang, Tianyu Xu, Daojing Gan, Zhuang Ma, Hao Zhang, Jian Zhang, Qingchun Zeng, Dingli Xu.
       AIMS: Sterile inflammation is implicated in the development of heart failure (HF). Mitochondria plays important roles in triggering and maintaining inflammation. Mitophagy is important for regulation of mitochondrial quality and maintenance of cardiac function under pressure overload. The association of mitophagy with inflammation in HF is largely unclear. As PINK1 is a central mediator of mitophagy, our objective was to investigate its involvement in cardiac hypertrophy, and the effect of PINK1-mediated mitophagy on cGAS-STING activation during cardiac hypertrophy.
    METHODS AND RESULTS: PINK1 knockout and cardiac-specific PINK1-overexpressing transgenic mice were created and subsequently subjected to transverse aortic constriction (TAC) surgery. In order to explore whether PINK1 regulates STING-mediated inflammation during HF, PINK1/STING (stimulator of interferon genes) double-knockout mice were created. Pressure overload was induced by TAC. Our findings indicate a significantly decline in PINK1 expression in TAC-induced hypertrophy. Cardiac hypertrophic stimuli caused the release of mitochondrial DNA (mtDNA) into the cytosol, activating the cGAS-STING signaling, which in turn initiated cardiac inflammation and promoted the progression of cardiac hypertrophy. PINK1 deficiency inhibited mitophagy activity, promoted mtDNA release, and then drove the overactivation of cGAS-STING signaling, exacerbating cardiac hypertrophy. Conversely, cardiac-specific PINK1 overexpression protected against hypertrophy thorough inhibition of the cGAS-STING signaling. Double-knockout mice revealed that the effects of PINK1 on hypertrophy were dependent on STING.
    CONCLUSIONS: Our findings suggest that PINK1-mediated mitophagy plays a protective role in pressure overload-induced cardiac hypertrophy via inhibiting the mtDNA-cGAS-STING pathway.
    Keywords:  Mitophagy; PINK1; STING; cardiac hypertrophy; inflammation
    DOI:  https://doi.org/10.1093/cvr/cvae238
  8. Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2414187121
    Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
    Mads M Foged, Emeline Recazens, Sylvain Chollet, Miriam Lisci, George E Allen, Boris Zinshteyn, Doha Boutguetait, Christian Münch, Vamsi K Mootha, Alexis A Jourdain.
      Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.
    Keywords:  OXPHOS; RNA processing; mitochondria; mitochondrial RNA granules; translation
    DOI:  https://doi.org/10.1073/pnas.2414187121
  9. Eur J Histochem. 2024 Oct 28. 68(4):
    Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction.
    Jinshuang Li, Dawei Xu, Ce Shi, Chunqi Cheng, Ziheng Xu, Xingjuan Gao, Yong Cheng.
      Heart failure with preserved ejection fraction (HFpEF), a complex disease that is increasingly prevalent due to population aging, pose significant challenges in its treatment. The present study utilized the HFpEF rat model and H9C2 cells as research subjects to thoroughly investigate the potential mechanisms of alarin in protecting cardiac function in HFpEF. The study shows that under HFpEF conditions, oxidative stress significantly increases, leading to myocardial structural damage and dysfunction of calcium ion channels, which ultimately impairs diastolic function. Alarin, through its interaction with NADPH oxidase 1 (NOX1), effectively alleviates oxidative stress and modulates the activities of type 2 ryanodine receptor (RyR2) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), thereby facilitating the restoration of Ca2+ homeostasis and significantly improving cardiac function in the HFpEF model. This research not only uncovers the cardioprotective effects of alarin and its underlying molecular mechanisms but also provides new insights and potential therapeutic targets for HFpEF treatment strategies, suggesting a promising future for alarin and related therapies in the management of this debilitating condition.
    DOI:  https://doi.org/10.4081/ejh.2024.4122
  10. Adv Sci (Weinh). 2024 Nov 03. e2405147
    HADHA Regulates Respiratory Complex Assembly and Couples FAO and OXPHOS.
    Chaoying Qin, Shasha Gong, Ting Liang, Zhenbo Zhang, Jessie Thomas, Janice Deng, Yaguang Liu, Peiqing Hu, Bi Zhu, Shujie Song, Marisol Fernández Ortiz, Yuji Ikeno, Exing Wang, James Lechleiter, Susan T Weintraub, Yidong Bai.
      Oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) are key bioenergetics pathways. The machineries for both processes are localized in mitochondria. Secondary OXPHOS defects have been documented in patients with primary FAO deficiencies, and vice versa. However, the underlying mechanisms remain unclear. Intrigued by the observations that regulation of supercomplexes (SCs) assembly in a mouse OXPHOS deficient cell line and its derivatives is associated with the changes in lipid metabolism, a proteomics analysis is carried out and identified mitochondrial trifunctional protein (MTP) subunit alpha (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, HADHA) as a potential regulatory factor for SCs assembly. HADHA-Knockdown cells and mouse embryonic fibroblasts (MEFs) derived from HADHA-Knockout mice displayed both reduced SCs assembly and defective OXPHOS. Stimulation of OXPHOS induced in cell culture by replacing glucose with galactose and of lipid metabolism in mice with a high-fat diet (HFD) both exhibited increased HADHA expression. HADHA Heterozygous mice fed with HFD showed enhanced steatosis associated with a reduction of SCs assembly and OXPHOS function. The results indicate that HADHA participates in SCs assembly and couples FAO and OXPHOS.
    Keywords:  HADHA; fatty acid oxidation (FAO); mitochondrial respiratory chain; mitochondrial trifunctional protein (MTP); respiratory complex I
    DOI:  https://doi.org/10.1002/advs.202405147
  11. Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2405020121
    Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility.
    Ankit Garg, Silvia Jansen, Lina Greenberg, Rui Zhang, Kory J Lavine, Michael J Greenberg.
      Skeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1's high expression in skeletal muscle. Rare de novo mutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ~20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 variant, R256H. We previously identified this variant in a family with dilated cardiomyopathy, who had reduced systolic function without clinical skeletal myopathy. Using a battery of multiscale biophysical tools, we show that R256H has potent effects on ACTA1 function at the molecular scale and in human cardiomyocytes. Importantly, we demonstrate that R256H acts in a dominant manner, where the incorporation of small amounts of mutant protein into thin filaments is sufficient to disrupt molecular contractility, and that this effect is dependent on the presence of troponin and tropomyosin. To understand the structural basis of this change in regulation, we resolved a structure of R256H filaments using cryoelectron microscopy, and we see alterations in actin's structure that have the potential to disrupt interactions with tropomyosin. Finally, we show that ACTA1R256H/+ human-induced pluripotent stem cell cardiomyocytes demonstrate reduced contractility and sarcomeric organization. Taken together, we demonstrate that R256H has multiple effects on ACTA1 function that are sufficient to cause reduced contractility and establish a likely causative relationship between ACTA1 R256H and clinical cardiomyopathy.
    Keywords:  actin; cardiomyopathy; contractility; muscle
    DOI:  https://doi.org/10.1073/pnas.2405020121
  12. Endocrinol Metab (Seoul). 2024 Nov 05.
    Prevalence of Subclinical Hypothyroidism in a Non-Diabetic Young Female Population and Its Impact on Diabetes and Cardiometabolic Risk.
    Nawoda Hewage, Udaya Wijesekara, Rasika Perera.
       Background: We evaluated the influence of subclinical hypothyroidism (SCH) on insulin resistance (IR), cardiometabolic risk, and obesity in childbearing-age women without diabetes.
    Methods: This cross-sectional investigation included 282 women, aged 18 to 35 years, from rural and suburban Sri Lanka. Anthropometric and biochemical parameters, including IR and lipid/thyroid profiles, were recorded. Data were compared between SCH and euthyroidism (EU) for controls (normal weight) and cases (overweight/obese).
    Results: The overall rates of SCH, EU, IR, and metabolic syndrome (MetS) were 40.42%, 59.57%, 73.40%, and 24.46%, respectively. Both controls and cases included individuals with SCH; overall, 168 participants (59.57%) had EU, while 114 (40.42%) exhibited SCH. IR was significantly associated with SCH in both weight groups (P<0.05). Among those with SCH, the odds ratios (ORs) for IR were >2 (95% confidence interval [CI], 0.45 to 3.87) in controls and >6 (95% CI, 3.52 to 8.41) in cases. Similarly, the ORs for MetS were >1 (95% CI, 0.38 to 4.16) in controls and >11 (95% CI, 8.73 to 15.01) in cases. Dyslipidemia and hypertriglyceridemia were significantly more prevalent in the SCH group (P<0.05). Women with SCH exhibited higher mean values for all obesity indices compared to their EU counterparts, surpassing normal thresholds (P<0.05). Among obesity measures, visceral adiposity index (VAI) demonstrated the highest area under the curve and sensitivity for assessing SCH and cardiovascular disease (CVD) risk.
    Conclusion: SCH must be identified and managed in young women to help prevent diabetes and cardiometabolic disorders. VAI may aid in precisely detecting SCH and CVD.
    Keywords:  Cardiometabolic risk; Cardiovascular diseases; Insulin resistance; Metabolic syndrome; Obesity; Subclinical hypothyroidism
    DOI:  https://doi.org/10.3803/EnM.2024.2015
  13. Sci Rep. 2024 11 06. 14(1): 26989
    GDF15 is required for maintaining subcutaneous adipose tissue lipid metabolic signature.
    Carla Igual-Gil, Christopher A Bishop, Markus Jähnert, Kornelia Johann, Verena Coleman, Vanessa Baum, Michael Kruse, Andreas F H Pfeiffer, Olga Pivovarova-Ramich, Mario Ost, Maximilian Kleinert, Susanne Klaus.
      Recent research has identified growth differentiation factor 15 (GDF15) as a crucial factor in various physiological and pathological processes, particularly in energy balance regulation. While the role of GDF15 in modulating energy metabolism through hindbrain GDNF family receptor alpha-like (GFRAL) signaling has been extensively studied, emerging evidence suggests direct peripheral metabolic actions of GDF15. Using knockout mouse models, we investigated GDF15 and GFRAL's roles in adipose tissue metabolism. Our findings indicate that C57BL/6/129/SvJ Gdf15-KO mice exhibit impaired expression of de novo lipogenesis enzymes in subcutaneous adipose tissue (sWAT). In contrast, C57BL/6J Gfral-KO mice showed no impairments compared to wild-type (WT) littermates. RNA-Seq analysis of sWAT in Gdf15-KO mice revealed a broad downregulation of genes involved in lipid metabolism. Importantly, our study uncovered sex-specific effects, with females being more affected by GDF15 loss than males. Additionally, we observed a fasting-induced upregulation of GDF15 gene expression in sWAT of both mice and humans, reinforcing this factor's role in adipose tissue lipid metabolism. In conclusion, our research highlights an essential role for GDF15 in sWAT lipid metabolic homeostasis. These insights enhance our understanding of GDF15's functions in adipose tissue physiology and underscore its potential as a therapeutic target for metabolic disorders.
    DOI:  https://doi.org/10.1038/s41598-024-77448-w
  14. iScience. 2024 Nov 15. 27(11): 111134
    A multiorgan map of metabolic, signaling, and inflammatory pathways that coordinately control fasting glycemia in mice.
    Florence Mehl, Ana Rodríguez Sánchez-Archidona, Ida Meitil, Mathias Gerl, Céline Cruciani-Guglielmacci, Leonore Wigger, Hervé Le Stunff, Kelly Meneyrol, Justine Lallement, Jessica Denom, Christian Klose, Kai Simons, Marco Pagni, Christophe Magnan, Mark Ibberson, Bernard Thorens.
      To identify the pathways that are coordinately regulated in pancreatic β cells, muscle, liver, and fat to control fasting glycemia we fed C57Bl/6, DBA/2, and Balb/c mice a regular chow or a high fat diet for 5, 13, and 33 days. Physiological, transcriptomic and lipidomic data were used in a data fusion approach to identify organ-specific pathways linked to fasting glycemia across all conditions investigated. In pancreatic islets, constant insulinemia despite higher glycemic levels was associated with reduced expression of hormone and neurotransmitter receptors, OXPHOS, cadherins, integrins, and gap junction mRNAs. Higher glycemia and insulin resistance were associated, in muscle, with decreased insulin signaling, glycolytic, Krebs' cycle, OXPHOS, and endo/exocytosis mRNAs; in hepatocytes, with reduced insulin signaling, branched chain amino acid catabolism and OXPHOS mRNAs; in adipose tissue, with increased innate immunity and lipid catabolism mRNAs. These data provide a resource for further studies of interorgan communication in glucose homeostasis.
    Keywords:  Bioinformatics; Omics; Physiology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111134
  15. J Am Heart Assoc. 2024 Nov 05. 13(21): e035193
    Sestrin2 Attenuates Myocardial Endoplasmic Reticulum Stress and Cardiac Dysfunction During Ischemia/Reperfusion Injury.
    Xuan Li, Zhen Wang, Alan J Mouton, Ana C M Omoto, Alexandre A da Silva, Jussara M do Carmo, Ji Li, John E Hall.
       BACKGROUND: Sesn2 (Sestrin2) is a stress-induced protein that provides protective effects during myocardial ischemia and reperfusion (I/R) injury, while endoplasmic reticulum (ER) stress may be a pivotal mediator of I/R injury. The goal of this study was to determine whether Sesn2-mTOR (mammalian target of rapamycin) signaling regulates ER stress during myocardial I/R.
    METHODS AND RESULTS: In vivo cardiac I/R was induced by ligation and subsequent release of the left anterior descending coronary artery in wild-type (WT) and cardiac-specific Sesn2 knockout (Sesn2cKO) mice. At 6 hours and 24 hours after reperfusion, cardiac function was evaluated, and heart samples were collected for analysis. I/R induced cardiac ER stress and upregulated Sesn2 mRNA and protein levels. Inhibiting ER stress with 4-phenylbutyric acid reduced infarct size by 37.5%, improved cardiac systolic function, and mitigated myocardial cell apoptosis post-I/R. Hearts from Sesn2cKO mice displayed increased susceptibility to ER stress during I/R compared with WT. Notably, cardiac mTOR signaling was further increased in Sesn2cKO hearts compared with WT hearts during I/R. In mice with cardiac Sesn2 deficiency, compared with WT, ER lumen was significantly expanded after tunicamycin-induced ER stress, as assessed by transmission electron microscopy. Additionally, pharmacological inhibition of mTOR signaling with rapamycin improved cardiac function after tunicamycin treatment and significantly attenuated the unfolded protein response and apoptosis in WT and Sesn2cKO mice.
    CONCLUSIONS: Sesn2 attenuates cardiac ER stress post-I/R injury via regulation of mTOR signaling. Thus, modulation of the mTOR pathway by Sesn2 could be a critical factor for maintaining cardiac ER homeostasis control during myocardial I/R injury.
    Keywords:  cardiac injury; heart; mTOR signaling; unfolded protein response
    DOI:  https://doi.org/10.1161/JAHA.124.035193
  16. Acta Pharmacol Sin. 2024 Nov 04.
    Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.
    Yao-Geng Wang, Chang-Pei Gan, Joke Beukers-Korver, Hilde Rosing, Wen-Long Li, Els Wagenaar, Maria C Lebre, Ji-Ying Song, Colin Pritchard, Rahmen Bin Ali, Ivo Huijbers, Jos H Beijnen, Alfred H Schinkel.
      Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2-/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2-/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2-/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2-/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2-/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a "healthy" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.
    Keywords:  capecitabine; carboxylesterase 2; glucose homeostasis; lipid metabolism; metabolic syndrome; vinorelbine
    DOI:  https://doi.org/10.1038/s41401-024-01407-4
  17. Obesity (Silver Spring). 2024 Nov;32(11): 1998-2011
    In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human visceral fat.
    Lijin Wang, Pratap Veerabrahma Seshachalam, Ruiming Chua, Hongwen Zhou, Sun Lei, Sujoy Ghosh.
       OBJECTIVE: Visceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk, and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene regulatory networks in human visceral obesity have been lacking.
    METHODS: We analyzed gene regulatory networks in human visceral adipose tissue (VAT) from 48 and 11 Chinese patients with and without obesity, respectively, using gene coexpression and gene regulatory network construction from RNA-sequencing data. We also conducted RNA interference-based functional tests on selected genes for effects on adipocyte differentiation.
    RESULTS: A scale-free gene coexpression network was constructed from 360 differentially expressed genes between VAT samples from patients with and without obesity (absolute log fold change > 1, false discovery rate [FDR] < 0.05), with edge probability > 0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. A total of 15 subnetworks (communities) displayed altered connectivity patterns between obesity and nonobesity networks. Genes in proinflammatory pathways showed increased network connectivity in VAT samples with obesity, whereas the oxidative phosphorylation pathway displayed reduced connectivity (enrichment FDR < 0.05). Functional screening via RNA interference identified genes such as SOX30, SIRPB1, and OSBPL3 as potential network-derived candidates influencing adipocyte differentiation.
    CONCLUSIONS: This approach highlights the network architecture in human obesity, identifies novel candidate genes, and generates new hypotheses regarding network-assisted gene regulation in VAT.
    DOI:  https://doi.org/10.1002/oby.24161
  18. Diabetes Ther. 2024 Nov 02.
    Treatment Patterns and Glycaemic Control Between 2015 and 2019 in Tianjin, China: A Real-World Study of Adults with Type 2 Diabetes.
    Qiumei Zhang, Yaqing Fan, Xixi Liu, Minlu Zhang, Jiewen Zhang, Qin Du, Lei Kang, Liming Chen.
       INTRODUCTION: Diabetes is associated with a high economic burden in China; therefore, strategies to prevent diabetes, improve glycaemic control, delay disease-related complications and maintain quality of life are essential. This study was conducted to evaluate trends in treatment patterns and glycaemic control in people with type 2 diabetes (T2D) in real-world clinical practice in Tianjin, China.
    METHODS: This retrospective, cross-sectional, multicentre study analysed data from adults with T2D living in Tianjin, China between 2015 and 2019, based on information obtained from a regional electronic medical record database. Temporal trends in treatment patterns and glycaemic control were assessed using linear regression (continuous variables), and Cochran-Armitage (two categories) or Cochran-Mantel-Haenszel (≥ 3 categories) tests.
    RESULTS: Between 2015 and 2019, data from 312,203 individuals treated at 75 hospitals were included. Over this period, there was an upward trend in the prevalence of hypertension, hyperlipidaemia, obesity, cardiovascular disease, stroke and retinopathy each year (all P < 0.001). The use of metformin or dipeptidyl peptidase-4 inhibitors increased, while thiazolidinedione, alpha-glucosidase inhibitor and glinide use decreased; the use of basal insulin (BI), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), GLP-1 RAs + BI, bolus insulin and BI + bolus insulin increased, whereas the use of premixed insulin showed a downward trend (all P < 0.001). From 2015 to 2019, an increased proportion of individuals achieved glycated haemoglobin (HbA1c) < 7% (< 53 mmol/mol; 28.1-33.7%), fasting plasma glucose (FPG) < 7 mmol/l (21.7-26.9%) and postprandial glucose (PPG) < 10 mmol/l (22.0-48.2%; all P < 0.001). There was no change in the proportion of individuals with an FPG ≥ 7 mmol/l and a PPG ≥ 10 mmol/l, while the prevalence of residual hyperglycaemia increased (P < 0.001).
    CONCLUSIONS: Glycaemic control improved between 2015 and 2019 in people with T2D in Tianjin, China; however, there is an unmet need for more effective glycaemic control.
    Keywords:  China; Glycaemic control; Real-world clinical practice; Temporal trends; Treatment patterns; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s13300-024-01661-z
  19. EJIFCC. 2024 Oct;35(3): 189-194
    Unveiling the Role of Magnesium: Insights into Insulin Resistance and Glycemic Control in Type 2 Diabetes.
    Vidya Sagar Ram, Ashutosh Vishnoi, Mimoh Sharma, Abel Jaison, Nivedita Singh.
       Background: Diabetes mellitus (DM) is a significant and escalating global health concern, with Type 2 DM (T2DM) constituting approximately 90% of all DM cases. Magnesium (Mg) plays a crucial role in various physiological processes. Hypomagnesemia is prevalent in T2DM patients. The severity of hypomagnesemia correlates with glycemic control and is linked to the development of complications associated with T2DM.
    Aim: The objective of our study was to evaluate the occurrence of hypomagnesemia in patients with T2DM and explore its association with both glycemic control and the development of complications in rural and urban populations.
    Methods: The study consisted of 300 diabetic and 100 non-diabetic patients between 31 and 55 years of age. Fasting blood glucose, post-prandial blood glucose, and magnesium levels were estimated using a fully automated analyzer, Selectra Pro-XL. HbA1c was measured using Bio-Rad D10. Insulin levels were calculated using the chemiluminescence method. HOMA-IR was also assessed using a formula: fasting insulin (U/mL) multiplied by fasting plasma glucose (FPG) (mmol/L) divided by 22.5.
    Result: Magnesium levels were significantly lower in diabetic patients (1.34±0.29) than in the control (2.17±1.87) with p<0.0001. FBS (267.67±89.78 mg/dL vs. 167.87±76.87 mg/dL, p<0.0001), PPBS (376.87±112.87 mg/dL vs. 287.90±99.98 mg/dL, p<0.0001), HbA1c (9.54±2.6 % vs. 7.23±1.8 %, p<0.0001), Insulin (17.21±8.98 IU/mL vs. 14.87±5.98 IU/ mL, p=0.039) and HOMA-IR (7.32±3.67 vs. 6.13±0.99, p=0.012) were significantly elevated in the hypomagnesemia group than the normal magnesium levels. Magnesium levels were negatively correlated with FBS (r=-0.465; p<0.0001), PPBS (r=-0.596; p<0.0001, HbA1c (r=-0.765; p<0.0001), Insulin (r=-0.454; p<0.0001), and HOMA-IR (r=-0.325; p<0.0001).
    Conclusion: Our study suggests that monitoring serum magnesium levels is crucial for individuals with Type 2 diabetes mellitus (T2DM) to manage hypomagnesemia, mitigate associated complications, and optimize overall care.
    Keywords:  Glucose Metabolism; Glycemic Control; HOMA-IR; Hypomagnesemia; T2DM
  20. Cardiovasc Diabetol. 2024 Nov 02. 23(1): 393
    Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial.
    Frank Qian, Yanjun Guo, Chunying Li, Yanyan Liu, Heike Luttmann-Gibson, Natalya Gomelskaya, Olga V Demler, Nancy R Cook, I-Min Lee, Julie E Buring, Julia Larsen, Jennifer Boring, Michael J McPhaul, JoAnn E Manson, Aruna D Pradhan, Samia Mora.
       BACKGROUND: Dysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.
    METHODS: VITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).
    RESULTS: We identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.
    CONCLUSIONS: Each of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.
    Keywords:  Cardiovascular disease; Insulin resistance; Omega-3 fatty acids; Type 2 diabetes; Vitamin D
    DOI:  https://doi.org/10.1186/s12933-024-02470-1
  21. J Lipid Res. 2024 Oct 25. pii: S0022-2275(24)00188-3. [Epub ahead of print] 100683
    Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.
    Jihui Ren, Robert Rieger, Nivea Pereira de Sa, Douglas Kelapire, Maurizio Del Poeta, Yusuf A Hannun.
      Sphingolipids (SPLs) are major components of cell membranes with significant functions. Their production is a highly-regulated multi-step process with the formation of two major intermediates, long chain bases (LCBs) and ceramides. Homologous Orm proteins in both yeast and mammals negatively regulate LCB production by inhibiting serine palmitoyltransferase (SPT), the first enzyme in SPL de novo synthesis. Orm proteins are therefore regarded as major regulator of SPL production. Combining targeted lipidomic profiling with phenotypic analysis of yeast mutants with both ORM1 and ORM2 deleted (orm1/2Δ), we report here that Ypk1, an AGC family protein kinase, signaling is compromised in an LCB-dependent manner. In orm1/2Δ, phosphorylation of Ypk1 at its activation sites is reduced, so does its in vivo activity shown by reduced phosphorylation of Ypk1 substrate, Lac1, the catalytic component of ceramide synthase (CerS). A corresponding defect in ceramide synthesis was detected, preventing the extra LCBs generated in orm1/2Δ from fully converting into downstream SPL products. The results suggest that Orm proteins play a complex role in regulating SPL production in yeast S. cerevisiae by exerting an extra and opposite effect on CerS. Functionally, we define an endocytosis and an actin polarization defect of orm1/2Δ and demonstrate the roles of Ypk1 in mediating the effects of Orm proteins on endocytosis. Collectively, the results reveal a previously unrecognized complexity of SPL de novo synthesis pathway and point to a potential role of Orm proteins as upstream regulators to control Ypk1-mediated biological functions via regulating LCB production.
    Keywords:  LCBs; Orm1/2; SPT; Ypk1; cell signaling; endocytosis; enzymology/enzyme regulation; lipidomics; lipids; sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100683
  22. MicroPubl Biol. 2024 ;2024
    Mitochondrial respiratory capacity is not altered in aging rat brains with or without memory impairment.
    Pamela J Yao, Jeffrey M Long, Peter R Rapp, Dimitrios Kapogiannis.
      Mitochondria are essential for supporting the high metabolic demands that are required for brain function. Impairments in mitochondria have been linked to age-related decline in brain functions. Here, we investigate whether the mitochondrial respiratory capacity of brain cells is changed in cognitive aging. We used a rat model of normal cognitive aging and analyzed mitochondrial oxidative phosphorylation in frozen brain samples. Mitochondrial oxygen consumption rate analysis of the frontal cortex did not show any differences between young rats and aged rats with either intact memory or impaired spatial memory. Mitochondrial ATP synthase activity and quantity also did not differ between young and aged rats. These results suggest that the total level of mitochondrial respiratory capacity is preserved in the frontal cortex of aged rats and may not explain aging-associated cognitive impairment.
    DOI:  https://doi.org/10.17912/micropub.biology.001359
  23. Adv Sci (Weinh). 2024 Nov 04. e2406695
    Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.
    Mengyi Wang, Shiwu Zhang, Jinwei Tian, Fan Yang, He Chen, Shuzhi Bai, Jiaxin Kang, Kemiao Pang, Jiayi Huang, Mingjie Dong, Shiyun Dong, Zhen Tian, Shaohong Fang, Huitao Fan, Fanghao Lu, Bo Yu, Shuijie Li, Weihua Zhang.
      Diabetic cardiomyopathy (DCM), a severe complication of diabetes, is characterized by mitochondrial dysfunction, oxidative stress, and DNA damage. Despite its severity, the intrinsic factors governing cardiomyocyte damage in DCM remain unclear. It is hypothesized that impaired iron-sulfur (Fe-S) cluster synthesis plays a crucial role in the pathogenesis of DCM. Reduced S-sulfhydration of cysteine desulfurase (NFS1) is a novel mechanism that contributes to mitochondrial dysfunction and PARthanatos in DCM. Mechanistically, hydrogen sulfide (H2S) supplementation restores NFS1 S-sulfhydration at cysteine 383 residue, thereby enhancing Fe-S cluster synthesis, improving mitochondrial function, increasing cardiomyocyte viability, and alleviating cardiac damage. This study provides novel insights into the interplay between Fe-S clusters, mitochondrial dysfunction, and PARthanatos, highlighting a promising therapeutic target for DCM and paving the way for potential clinical interventions to improve patient outcomes.
    Keywords:  PARthanatos; cysteine desulfurase (NFS1); diabetic cardiomyopathy (DCM); hydrogen sulfide (H2S); iron–sulfur (Fe–S) cluster
    DOI:  https://doi.org/10.1002/advs.202406695
  24. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  25. Intern Med. 2024 Nov 01.
    Effects of ipragliflozin on skeletal muscle adiposity in patients with diabetes and metabolic dysfunction-associated steatotic liver disease.
    Yuko Ishimaru, Takaomi Kessoku, Michihiro Nonaka, Yoichiro Kitajima, Hideyuki Hyogo, Tomoaki Nakajima, Kento Imajo, Yoshihito Kubotsu, Hiroshi Isoda, Miwa Kawanaka, Masato Yoneda, Keizo Anzai, Atsushi Nakajima, Kyoji Furukawa, Atsushi Kawaguchi, Hirokazu Takahashi.
      Objective Myosteatosis affects the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and may be a potential therapeutic target. This study aimed to examine the effects of ipragliflozin on myosteatosis in patients with type 2 diabetes mellitus (T2D) and MASLD. Methods Patients were treated with ipragliflozin (IPR group) or a control (CTR group) for 72 weeks in a randomized trial. Changes in myosteatosis of the lumbar skeletal muscles were evaluated using computed tomography (CT). The response of myosteatosis to treatment and the baseline characteristics of the patients were analyzed. Patients 44 participants (IPR group, 23; CTR group, 21) with MASLD complicated by T2D Results Myosteatosis increased in the CTR group (n=23) but remained unchanged in the IPR group (n=21). The changes were apparent at 24 weeks (P=0.004), but were not significant after 24 weeks. A hierarchical cluster analysis was performed to identify clusters with and without improvement in myosteatosis. The clusters with decreasing intramuscular adipose tissue content (IMAC) at 48 and 72 weeks were not treated, but they had lower visceral fat area and severe liver steatosis at baseline. Improvements in glycemic control and resistance to decreasing abdominal skeletal muscle area from baseline to 24 weeks affected the decrease in IMAC at 48 and 72 weeks. Conclusion Ipragliflozin had a limited effect on skeletal muscle adiposity in patients with T2D and MASLD. Regardless of the treatment, a specific phenotype of adiposity and hepatic steatosis before treatment is associated with the long-term outcomes of myosteatosis. Maintaining skeletal muscle mass and better glycemic control during treatment are essential for the future improvement of myosteatosis.
    Keywords:  myosteatosis; sarcopenia; sodium glucose cotransporter-2 inhibitors; subcutaneous fat; visceral fat
    DOI:  https://doi.org/10.2169/internalmedicine.4456-24
  26. Methods Enzymol. 2024 ;pii: S0076-6879(24)00388-4. [Epub ahead of print]707 475-498
    Analysis of mitochondrial protein aggregation and disaggregation.
    Wolfgang Voos, Anne Wilkening, Robin Ostermann, Michael Bruderek, Witold Jaworek, Laura Ruland.
      Deficits of mitochondrial functions have been identified in many human pathologies, in particular in age-related human neurodegenerative diseases. Hence, the molecular causes for mitochondrial dysfunction and potential protection mechanisms have become a major topic in modern cell biology. Apart from defects in their structural integrity, problems in mitochondrial protein biogenesis, including polypeptide transport, folding and assembly to active enzymes, all may result in some degree of functional defects of the organelle. An accumulation of misfolded polypeptides inside mitochondria, confounded by the dual source of mitochondrial polypeptides, will result in the formation of protein aggregates. Such aggregate accumulation bears a cell-toxic potential, resulting in mitochondrial and correlated cellular damages, summarized in the term "aggregate proteotoxicity". Here, we discuss methods to analyze protein aggregation in the mitochondrial matrix compartment. We also address techniques to characterize the biochemical mechanisms that reduce aggregate proteotoxicity, the disaggregation or resolubilization of aggregated polypeptides and the sequestration and neutralization of mitochondrial aggregates at specific sites inside a cell.
    Keywords:  ATP-dependent proteases; Human cells; Mitochondria; Molecular chaperones; Protein aggregation; Proteotoxicity; Yeast
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.048
  27. Mol Metab. 2024 Nov 04. pii: S2212-8778(24)00183-2. [Epub ahead of print] 102052
    GLIS3: a novel transcriptional regulator of mitochondrial functions and metabolic reprogramming in postnatal kidney and polycystic kidney disease.
    Justin B Collier, Hong Soon Kang, Yun-Gil Roh, Chitrangda Srivastava, Sara A Grimm, Alan K Jarmusch, Anton M Jetten.
       BACKGROUND AND AIMS: Deficiency in the transcription factor (TF) GLI-Similar 3 (GLIS3) in humans and mice leads to the development of polycystic kidney disease (PKD). In this study, we investigate the role of GLIS3 in the regulation of energy metabolism and mitochondrial functions in relation to its role in normal kidney and metabolic reprogramming in PKD pathogenesis.
    APPROACH AND RESULTS: Transcriptomics, cistromics, and metabolomics were used to obtain insights into the role of GLIS3 in the regulation of energy homeostasis and mitochondrial metabolism in normal kidney and PKD pathogenesis using GLIS3-deficient mice. Transcriptome analysis showed that many genes critical for mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and the tricarboxylic acid (TCA) cycle, including Tfam, Tfb1m, Tfb2m, Ppargc1a, Ppargc1b, Atp5j2, Hadha, and Sdha, are significantly suppressed in kidneys from both ubiquitous and tissue-specific Glis3-deficient mice. ChIP-Seq analysis demonstrated that GLIS3 is associated with the regulatory region of many of these genes, indicating that their transcription is directly regulated by GLIS3. Cistrome analyses revealed that GLIS3 binding loci frequently located near those of hepatocyte nuclear factor 1-Beta (HNF1B) and nuclear respiratory factor 1 (NRF1) suggesting GLIS3 regulates transcription of many metabolic and mitochondrial function-related genes in coordination with these TFs. Seahorse analysis and untargeted metabolomics corroborated that mitochondrial OXPHOS utilization is suppressed in GLIS3-deficient kidneys and showed that key metabolites in glycolysis, TCA cycle, and glutamine pathways were altered indicating increased reliance on aerobic glycolysis and glutamine anaplerosis. These features of metabolic reprogramming may contribute to a bioenergetic environment that supports renal cyst formation and progression in Glis3-deficient mice kidneys.
    CONCLUSIONS: We identify GLIS3 as a novel positive regulator of the transition from aerobic glycolysis to OXPHOS in normal early postnatal kidney development by directly regulating the transcription of mitochondrial metabolic genes. Loss of GLIS3 induces several features of renal cell metabolic reprogramming. Our study identifies GLIS3 as a new participant in an interconnected transcription regulatory network, that includes HNF1B and NRF1, critical in the regulation of mitochondrial-related gene expression and energy metabolism in normal postnatal kidneys and PKD pathogenesis in Glis3-deficient mice.
    Keywords:  Aerobic glycolysis; GLIS3; Metabolic reprogramming; Oxidative phosphorylation; Polycystic kidney disease; Transcription
    DOI:  https://doi.org/10.1016/j.molmet.2024.102052
  28. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00400-5. [Epub ahead of print]
    Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes.
    Victor Gray, Weixin Chen, Rachael Julia Yuenyinn Tan, Jia Ming Nickolas Teo, Zhihao Huang, Carol Ho-Yi Fong, Tommy Wing Hang Law, Zi-Wei Ye, Shuofeng Yuan, Xiucong Bao, Ivan Fan-Ngai Hung, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.
      Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+ T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+ T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.
    Keywords:  T helper 1 responses; hyperglycemia; lipid peroxidation; protein carbonylation; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.004
  29. Asian Cardiovasc Thorac Ann. 2024 Nov 03. 2184923241296166
    Coronary arteriovenous fistula originating from the left coronary artery and draining into the superior vena cava.
    Airi Kageyama, Takayuki Saito.
      Coronary arteriovenous fistulas are rare coronary anomalies. Most fistulas arise from the right coronary artery and drain into the right heart structures. We report a case of a 59-year-old man with a rare coronary arteriovenous fistula that originates from the left coronary artery and drains into the superior vena cava. He was diagnosed incidentally with cardiac computed tomography during the investigation for atrial fibrillation. Surgical fistula ligation was successfully performed under cardiac arrest with cardiopulmonary bypass. The patient was discharged without complications.
    Keywords:  Coronary arteriovenous fistula; congenital heart disease; coronary artery fistula); coronary disease (including anomalous coronary artery from the pulmonary artery; left coronary artery; superior vena cava
    DOI:  https://doi.org/10.1177/02184923241296166
  30. Transl Gastroenterol Hepatol. 2024 ;9 62
    REGγ deficiency ameliorates hepatic ischemia and reperfusion injury in a mitochondrial p66shc dependent manner in mice.
    Long Guo, Qing Yang, Jiali Zhu, Jinbao Li.
       Background: Hepatic ischemia and reperfusion (I/R) injury is a common problem faced by patients undergoing clinical liver transplantation and hepatectomy, but the specific mechanism of liver I/R injury has not been fully elucidated. The protein degradation complex 11S proteasome is involved in apoptosis, proliferation and cell cycle regulation by regulating the 11S proteasome regulatory complex (REG)γ. The main objective of this study is to explore the role and specific mechanism of REGγ in liver I/R.
    Methods: By constructing a model of in vivo hepatic I/R injury in mice and a model of hypoxia and reoxygenation (H/R) in isolated hepatocytes. First, the REGγ expression were detected during hepatic I/R in mice. Second, to investigate the effects of REGγ knockout (KO) on liver necrosis, inflammatory response, apoptosis and mitochondrial function. Finally, mouse liver Src homology collagen (p66shc) mitochondrial translocation was detected.
    Results: The expression of REGγ was up-regulated during hepatic I/R. REGγ KO had significantly reduced liver tissue infarct size, liver transaminases, inflammatory cells infiltration, inflammatory cytokine and activation of nuclear factor kappa-B (NF-κB) signaling pathway and cell apoptosis. REGγ KO had significantly alleviated the mitochondrial damage, decreased the up-regulated level of cytochrome C, reactive oxygen species (ROS). REGγ KO had significantly reduced p66shc mitochondrial translocation in mice.
    Conclusions: The experimental results of this study indicated that REGγ has an important role in preventing liver I/R injury and may play a role through the mitochondrial p66shc signaling pathway.
    Keywords:  Ischemia and reperfusion (I/R); apoptosis; mitochondrial function; p66shc; the 11S proteasome regulatory complex γ (REGγ)
    DOI:  https://doi.org/10.21037/tgh-24-46
  31. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 31. pii: S0925-4439(24)00550-7. [Epub ahead of print]1871(1): 167556
    Mitochondrial respiratory complex II is altered in renal carcinoma.
    Sona Miklovicova, Luca Volpini, Ondrej Sanovec, Federica Monaco, Katerina Hadrava Vanova, Jaromir Novak, Stepana Boukalova, Renata Zobalova, Petr Klezl, Marco Tomasetti, Vladimir Bobek, Vojtech Fiala, Josef Vcelak, Lory Santarelli, Zuzana Bielcikova, Katerina Komrskova, Katarina Kolostova, Karel Pacak, Sarka Dvorakova, Jiri Neuzil.
       BACKGROUND: Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients.
    METHODS: We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients.
    RESULTS: ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue.
    CONCLUSIONS: Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.
    Keywords:  Complex II; Metabolism; Mitochondria; Organoids; Renal cell carcinoma; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167556
  32. Nat Commun. 2024 Nov 02. 15(1): 9475
    CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
    Chuanhai Zhang, Mengchen Ye, Kamran Melikov, Dengbao Yang, Goncalo Dias do Vale, Jeffrey McDonald, Kaitlyn Eckert, Mei-Jung Lin, Xing Zeng.
      Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.
    DOI:  https://doi.org/10.1038/s41467-024-53750-z
  33. ESC Heart Fail. 2024 Nov 05.
    Metabolic abnormalities and reprogramming in cats with naturally occurring hypertrophic cardiomyopathy.
    Qinghong Li, Max Homilius, Erin Achilles, Laura K Massey, Victoria Convey, Åsa Ohlsson, Ingrid Ljungvall, Jens Häggström, Brittany Vester Boler, Pascal Steiner, Sharlene Day, Calum A MacRae, Mark A Oyama.
       BACKGROUND AND AIMS: The heart is a metabolic organ rich in mitochondria. The failing heart reprograms to utilize different energy substrates, which increase its oxygen consumption. These adaptive changes contribute to increased oxidative stress. Hypertrophic cardiomyopathy (HCM) is a common heart condition, affecting approximately 15% of the general cat population. Feline HCM shares phenotypical and genotypical similarities with human HCM, but the disease mechanisms for both species are incompletely understood. Our goal was to characterize global changes in metabolome between healthy control cats and cats with different stages of HCM.
    METHODS: Serum samples from 83 cats, the majority (70/83) of which were domestic shorthair and included 23 healthy control cats, 31 and 12 preclinical cats with American College of Veterinary Internal Medicine (ACVIM) stages B1 and B2, respectively, and 17 cats with history of clinical heart failure or arterial thromboembolism (ACVIM stage C), were collected for untargeted metabolomic analysis. Multiple linear regression adjusted for age, sex and body weight was applied to compare between control and across HCM groups.
    RESULTS: Our study identified 1253 metabolites, of which 983 metabolites had known identities. Statistical analysis identified 167 metabolites that were significantly different among groups (adjusted P < 0.1). About half of the differentially identified metabolites were lipids, including glycerophospholipids, sphingolipids and cholesterol. Serum concentrations of free fatty acids, 3-hydroxy fatty acids and acylcarnitines were increased in HCM groups compared with control group. The levels of creatine phosphate and multiple Krebs cycle intermediates, including succinate, aconitate and α-ketoglutarate, also accumulated in the circulation of HCM cats. In addition, serum levels of nicotinamide and tryptophan, precursors for de novo NAD+ biosynthesis, were reduced in HCM groups versus control group. Glutathione metabolism was altered. Serum levels of cystine, the oxidized form of cysteine and cysteine-glutathione disulfide, were elevated in the HCM groups, indicative of heightened oxidative stress. Further, the level of ophthalmate, an endogenous glutathione analog and competitive inhibitor, was increased by more than twofold in HCM groups versus control group. Finally, several uremic toxins, including guanidino compounds and protein bound putrescine, accumulated in the circulation of HCM cats.
    CONCLUSIONS: Our study provided evidence of deranged energy metabolism, altered glutathione homeostasis and impaired renal uremic toxin excretion. Altered lipid metabolism suggested perturbed structure and function of cardiac sarcolemma membrane and lipid signalling.
    Keywords:  NAD; energy metabolism; feline; glutathione; lipid; uremic toxin
    DOI:  https://doi.org/10.1002/ehf2.15135
  34. World J Diabetes. 2024 Oct 15. 15(10): 2135-2146
    Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes: A systematic review with multiple network meta-regressions.
    Jing-Jing Zhu, John P H Wilding, Xiao-Song Gu.
       BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are associated with significant cardiovascular benefit in type 2 diabetes (T2D). However, GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.
    AIM: To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.
    METHODS: The systematic review was conducted according to PRISMA recommendations. The protocol was registered on PROSPERO (ID: 42022385007). A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment. Effect modification of prior myocardial infarction (MI) and heart failure (HF) was also explored to provide clinical insight as to when the combination treatment should be considered.
    RESULTS: The estimated hazard ratios (HR)GLP-1RA/SGLT-2I vs Placebo (0.75-0.98) and HRCombination vs GLP-1RA/SGLT-2I (0.26-0.86) for primary and secondary cardiovascular outcomes suggested that the combination treatment may achieve additional cardiovascular benefit compared with GLP-1RA or SGLT-2I alone. In patients with prior MI or HF, the mono-therapies may not improve the overall cardiovascular outcomes, as the estimated HRMI+/HF+ (0.57-1.52) suggested that GLP-1RA or SGLT-2I alone may be associated with lower risks of hospitalization for HF but not cardiovascular death.
    CONCLUSION: Considering its greater cardiovascular benefit in T2D, the combination treatment of GLP-1RA and SGLT-2I might be prioritized in patients with prior MI or HF, where the monotherapies may not provide sufficient cardiovascular protection.
    Keywords:  Cardiovascular outcome; Combination treatment; Glucagon-like peptide-1 receptor agonist; Network meta-regression; Sodium-glucose co-transporter-2 inhibitor; Systematic review; Type 2 diabetes
    DOI:  https://doi.org/10.4239/wjd.v15.i10.2135
  35. Curr Biol. 2024 Nov 04. pii: S0960-9822(24)01346-0. [Epub ahead of print]34(21): R1067-R1068
    Mitochondrial nucleoids.
    Eve V Kakudji, Samantha C Lewis.
      Eve Kakudji and Samantha Lewis discuss the structure and function of mitochondrial nucleoids - large nucleoprotein complexes containing mitochondrial DNA and the regulatory factors necessary for its packaging, replication, transcription, and repair.
    DOI:  https://doi.org/10.1016/j.cub.2024.09.078
  36. Methods Enzymol. 2024 ;pii: S0076-6879(24)00405-1. [Epub ahead of print]707 519-539
    Analysis of mitochondrial biogenesis regulation by oxidative stress.
    Dheeraj Pathak, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.
      Of all the causes of metabolic and neurological disorders, oxidative stress distinguishes itself by its sweeping effect on the dynamic cellular redox homeostasis and, in its wake, exposing the vulnerabilities of the protein machinery of the cell. High levels of Reactive Oxygen Species (ROS) that mitochondria produce during ATP synthesis can damage mtDNA, lipids, and essential mitochondrial proteins. ROS majorly oxidizes cysteine and methionine amino acids in peptides, which can lead to protein unfolding or misfolding of proteins, which ultimately can have a toll on their function. As mitochondrial biogenesis relies on the continuous import of nuclear-encoded proteins into mitochondria mediated by mitochondrial protein import complexes, oxidative stress triggered by mitochondria can rapidly and detrimentally affect mitochondrial biogenesis and homeostasis. Functional Mge1 is a homodimer and acts as a cochaperone and a nucleotide exchange factor of mitochondrial heat shock protein 70 (mHsp70), crucial for mitochondrial protein import. Oxidative stress like ROS, oxidizes Met 155 in Mge1, compromising its ability to dimerize and interact with mHsp70. The cell employs Methionine sulphoxide reductase 2 (Mxr2), a member of the methionine sulphoxide reductase family, to reduce oxidized Met 155 and thereby restore the essential function of Mge1. Oxidation of methionine as a regulated post-translational modification has been gaining traction. Future high throughput studies that can scan the entire mitochondrial proteome to interrogate methionine oxidation and reversal may increase the repertoire of mitochondrial proteins undergoing regulated oxidation and reduction. In this chapter, we describe the methods followed in our laboratory to study the oxidation of Mge1 and its reduction by Mxr2 in vitro.
    Keywords:  Cross linking; Methionine oxidation; Methionine sulfoixde reductase 2; Mge1; Mitochondria; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.060
  37. Methods Enzymol. 2024 ;pii: S0076-6879(24)00387-2. [Epub ahead of print]707 173-208
    Monitoring retro-translocation of proteins from the mitochondrial intermembrane space.
    Magda Krakowczyk, Piotr Bragoszewski.
      Mitochondria play multiple essential roles in eukaryotic cells. To perform their functions, mitochondria require an adequate supply of externally produced proteins and an intact two-membrane structure. The structure of mitochondrial membranes separates these organelles from their cytosolic environment, with proteins that make up the mitochondrial proteome either being embedded into or enveloped by these membranes. From the experimental point of view, the structural properties of mitochondria contribute to the relative ease of isolating these organelles from other cellular components. The ability to isolate intact mitochondria and analyze them in a well-controlled environment opens up the possibility of tracking any proteins that enter or escape the membrane-formed enclosure. This chapter discusses assays that monitor the movement of proteins out of mitochondria through intact membranes. These protocols provide insight into the mechanisms behind mitochondrial protein quality control. It was discovered that the retro-translocation of IMS proteins regulates the protein content of this specific sub-compartment of the organelle. Additionally, proteins can move out of the mitochondria to resolve failed import events. Assays based on isolated mitochondria precisely tackle such intricate 'dance' of proteins crossing mitochondrial membranes during import and export, maintaining the dynamics of the organellar proteome.
    Keywords:  Intermembrane space; MIA pathway; Mitochondria; Protease; Protein import; Protein quality control; Protein retro-translocation; Protein transport; Proteostasis
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.047
  38. Redox Rep. 2024 Dec;29(1): 2420564
    Resveratrol relieves myocardial ischemia-reperfusion injury through inhibiting AKT nitration modification.
    Lei Li, Jiantao Wang, Dandan Zhang, Li Deng, Xudong Zhao, Chunqing Wang, Xianliang Yan, Shuqun Hu.
       OBJECTIVE: The aim of this study was to clarify whether Protein kinase B (PKB)/AKT is nitrated in myocardial ischemia and reperfusion injury (MIRI) resveratrol (RSV)'s protective effect during this process.
    METHODS: We blocked blood flow of the left coronary artery (LAD) of mice and used H9c2 cells under an oxygen-glucose deprivation (OGD) environment as animal and cell models of MIRI. N-methyl-D-aspartic acid receptor (NMDAR) inhibitor MK801, neuronal nitric oxide synthase (nNOS) inhibitor 7-NI and RSV were used as interventions. Nitration of proteins, infarction area, cardiomyocyte apoptosis and AKT nitration sites were detected during this study.
    RESULTS: During in-vivo study, AKT nitration was induced through the NMDAR/nNOS/peroxynitrite (ONOO-) pathway, leading to decreased phosphorylation of AKT and increased cardiomyocyte apoptosis. AKT nitration was decreased and phosphorylation was elevated when administrated with RSV, MK801 and 7-NI. In in-vitro study, AKT nitration and TUNEL positive cells was elevated when administrated with NO donor H9c2 cells after OGD/R, when administrated with RSV, MK801 and 7-NI, AKT nitration and apoptosis was deceased in H9c2 cells. Mass spectrometry revealed that nitration sites of AKT included 14 Tyrosine residues.
    DISCUSSION: RSV could inhibit AKT nitration and elevated phosphorylation through suppressing NMDAR/nNOS/ONOO- pathway and further reduce the apoptosis of cardiomyocytes in of myocardial I/R.
    Keywords:  AKT; N-methyl-D-aspartic acid receptor (NMDAR); myocardial ischemia–reperfusion; nitration; oxidative stress; peroxynitrite (ONOO–); resveratrol; ‌neuronal nitric oxide synthase (nNOS)
    DOI:  https://doi.org/10.1080/13510002.2024.2420564
  39. J Nutr Health Aging. 2024 Nov 05. pii: S1279-7707(24)00496-2. [Epub ahead of print]28(12): 100408
    Mitochondrial quality control measures, systemic inflammation, and lower-limb muscle power in older adults: a PROMPT secondary analysis.
    Helio José Coelho-Junior, Emanuele Marzetti, Casey L Sexton, Kevin Wu, Robert Mankowski, Stephen D Anton, Christiaan Leeuwenburgh, Anna Picca.
       OBJECTIVES: The study was conducted to explore associations between markers of mitochondrial quality control (MQC) from vastus lateralis muscle biopsies, serum inflammatory markers, and measures of muscle power assessed by two different tools in a sample of older adults.
    DESIGN: Secondary analysis of data collected in the PeppeR develOpMental ProjecT (PROMPT) at the University of Florida (Gainesville, FL, USA).
    METHODS: Forty-three older adults (n = 20 women) were included in the study. Muscle volume of the calf and thigh was quantified by three-dimensional magnetic resonance imaging. Lower-limb muscle power was estimated using 5-time sit-to-stand (5STS) muscle power equations and isokinetic test. Protein markers of MQC were measured in muscle samples by Western immoblotting (n = 12-23), while type I and II fiber cross-sectional area (CSA) and their proportion were quantified using immunohistochemistry (n = 12). Cytochrome C oxidase enzyme activity was measured spectrophotometrically. Finally, inflammatory markers were quantified in the serum using a multiplex immunoassay (n = 39).
    RESULTS: Mean age of participants was 78.1 ± 5.5 years, and the average body mass index was 26.2 ± 4.5 kg/m2. Markers of mitochondrial biogenesis (i.e., PGC-1α), mitochondrial import proteins (i.e., cHsp70 and mtHsp70), and type I fiber CSA were significantly associated with muscle power estimated via both 5STS muscle power equations and isokinetic test (p < 0.05). Specific associations were also found according to the muscle power assessment method. 5STS muscle power measures were negatively correlated with ClvCasp3, P-AMPK, T-AMPK, P-p38, GM-CSF, INF-γ, IL1b, IL6, IL8, and TNF-α, whereas positive associations were found with BAX (p < 0.05). In contrast, isokinetic measures were significantly and positively correlated with RIP140, Hsp60, and type II muscle fiber CSA (p < 0.05).
    CONCLUSIONS: Markers of mitochondrial biogenesis (PGC-1α), mitochondrial import proteins (cHsp70 and mtHsp70), and type I muscle fiber CSA were significantly linked to lower-limb muscle power in older adults. These results suggest that muscle power is influenced by mitochondrial signaling. We also found that the relationship between mitochondrial mediators, inflammatory markers, and muscle power varied according to the assessment tool used.
    Keywords:  Apoptosis; Inflammaging; Mitochondria; Muscle aging; Physical performance; Sarcopenia
    DOI:  https://doi.org/10.1016/j.jnha.2024.100408
  40. Obesity (Silver Spring). 2024 Nov;32(11): 2024-2034
    Machine learning-based clustering identifies obesity subgroups with differential multi-omics profiles and metabolic patterns.
    Mohammad Y Anwar, Heather Highland, Victoria Lynn Buchanan, Mariaelisa Graff, Kristin Young, Kent D Taylor, Russell P Tracy, Peter Durda, Yongmei Liu, Craig W Johnson, Francois Aguet, Kristin G Ardlie, Robert E Gerszten, Clary B Clish, Leslie A Lange, Jingzhong Ding, Mark O Goodarzi, Yii-Der Ida Chen, Gina M Peloso, Xiuqing Guo, Maggie A Stanislawski, Jerome I Rotter, Stephen S Rich, Anne E Justice, Ching-Ti Liu, Kari North.
       OBJECTIVE: Individuals living with obesity are differentially susceptible to cardiometabolic diseases. We hypothesized that an integrative multi-omics approach might improve identification of subgroups of individuals with obesity who have distinct cardiometabolic disease patterns.
    METHODS: We performed machine learning-based, integrative unsupervised clustering to identify proteomics- and metabolomics-defined subpopulations of individuals living with obesity (BMI ≥ 30 kg/m2), leveraging data from 243 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Omics that contributed to the observed clusters were functionally characterized. We performed multivariate regression to assess whether the individuals in each cluster demonstrated differential patterns of cardiometabolic traits.
    RESULTS: We identified two distinct clusters (iCluster1 and 2). iCluster2 had significantly higher average BMI values, fasting blood glucose, and inflammation. iCluster1 was associated with higher levels of total cholesterol and high-density lipoprotein cholesterol. Pathways mediating cell growth, lipogenesis, and energy expenditures were positively associated with iCluster1. Inflammatory response and insulin resistance pathways were positively associated with iCluster2.
    CONCLUSIONS: Although the two identified clusters may represent progressive obesity-related pathologic processes measured at different stages, other mechanisms in combination could also underpin the identified clusters given no significant age difference between the comparative groups. For instance, clusters may reflect differences in dietary/behavioral patterns or differential rates of metabolic damage.
    DOI:  https://doi.org/10.1002/oby.24137
  41. JAMA Cardiol. 2024 Nov 06.
    Heart Failure With Preserved Ejection Fraction-A Role for Invasive Hemodynamics.
    Gregg C Fonarow, James E Udelson, Clyde W Yancy.
      
    DOI:  https://doi.org/10.1001/jamacardio.2024.3764
  42. Methods Enzymol. 2024 ;pii: S0076-6879(24)00400-2. [Epub ahead of print]707 39-62
    Monitoring α-helical membrane protein insertion into the outer mitochondrial membrane of yeast cells.
    Isabelle Steymans, Thomas Becker.
      Mitochondria are surrounded by two membranes, the outer and inner membrane. The outer membrane contains a few dozen integral membrane proteins that mediate transport, fusion and fission processes, form contact sites and are involved in signaling pathways. There are two different types of outer membrane proteins. A few proteins are membrane-integrated by a transmembrane β-barrel, while other proteins are embedded by single or multiple α-helical membrane segments. All outer membrane proteins are produced on cytosolic ribosomes, but their import mechanisms differ. The translocase of the outer mitochondrial membrane (TOM complex) and the sorting and assembly machinery (SAM complex) import β-barrel proteins. Different import pathways have been reported for proteins with α-helical membrane anchors. The mitochondrial import (MIM) complex is the major insertase for this type of proteins. The in vitro import of radiolabeled precursor proteins into isolated mitochondria is a versatile technique to study protein import into the outer mitochondrial membrane. The import of these proteins does not involve proteolytic processing and is not dependent on the membrane potential. Therefore, the import assay has to be combined with blue native electrophoresis, carbonate extraction or protease accessibility assays to determine the import efficiency. These techniques allow to define import steps, assembly intermediates and study membrane integration. The in vitro import assay has been a central tool to uncover specific import routes and mechanisms.
    Keywords:  MIM complex; Mitochondria; Protein sorting; SAM complex; TOM complex
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.055
  43. Clin Chem. 2024 Nov 04. 70(11): 1393-1394
    Proteinuria, Blinded by Bright Light.
    Mirthe Ubink, Judith Y M N Derijks-Engwegen, Miranda van Berkel, Harm Westdorp, Joannes F M Jacobs.
      
    DOI:  https://doi.org/10.1093/clinchem/hvae111
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