bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2025–01–12
twelve papers selected by
Henver Brunetta, Karolinska Institutet
  1. Adipose ZFP36 protects against diet-induced obesity and insulin resistance.
  2. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  3. Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis.
  4. PINK1 modulates Prdx2 to reduce lipotoxicity-induced apoptosis and attenuate cardiac dysfunction in heart failure mice with a preserved ejection fraction.
  5. Formation of I2+III2 supercomplex rescues respiratory chain defects.
  6. Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
  7. Time-resolved effects of short-term overfeeding on energy balance in mice.
  8. The protective effects of liraglutide in reducing lipid droplets accumulation and myocardial fibrosis in diabetic cardiomyopathy.
  9. Heart Failure with Preserved Ejection Fraction.
  10. Mitochondrial YME1L1 governs unoccupied protein translocase channels.
  11. Enhancing adipose tissue plasticity: progenitor cell roles in metabolic health.
  12. Burdens of type 2 diabetes and cardiovascular disease attributable to sugar-sweetened beverages in 184 countries.
  1. Metabolism. 2025 Jan 04. pii: S0026-0495(24)00359-7. [Epub ahead of print]164 156131
    Adipose ZFP36 protects against diet-induced obesity and insulin resistance.
    Yang Hu, Jinghan Hai, Yun Ti, Binghui Kong, Guoqing Yao, Yuan Zhao, Chen Zhang, Xuehui Zheng, Chunmei Zhang, Xiangping Ma, Huaitao Yu, Xiaoning Qin, Pavel Kovarik, Cheng Zhang, Shaozhuang Liu, Wencheng Zhang, Jingyuan Li, Peili Bu.
       AIMS: Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.
    METHODS: The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36AKO) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.
    RESULTS: Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression.
    CONCLUSIONS: This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.
    Keywords:  Adipose; Hypoxia; Lipolysis; Obesity; RNF128; Sirt1; ZFP36
    DOI:  https://doi.org/10.1016/j.metabol.2024.156131
  2. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  3. Diabetes Obes Metab. 2025 Jan 06.
    Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis.
    Kieren J Mather, Andrea Mari, Govinda Weerakkody, Tim Heise, J Hans DeVries, Shweta Urva, Tamer Coskun, Zvonko Milicevic, Axel Haupt, Melissa K Thomas.
       AIMS: To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide.
    MATERIALS AND METHODS: We conducted a post hoc exploratory analysis of a 28-week, double-blind, randomized trial in people with type 2 diabetes treated with metformin, randomized to tirzepatide 15 mg, semaglutide 1 mg or placebo. We evaluated the relationship between change in body weight and change in insulin sensitivity determined from hyperinsulinemic euglycemic clamp (M value), or from mixed-meal tolerance testing (Matsuda index).
    RESULTS: Tirzepatide was associated with a greater improvement than semaglutide in insulin sensitivity assessed using hyperinsulinemic euglycemic clamps (p < 0.001). With tirzepatide, improvements in insulin sensitivity were associated with percent change in weight (R = -0.656, p < 0.0001). With semaglutide, change in insulin sensitivity was less strongly correlated with percent change in weight (R = -0.268, p = 0.0820; p = 0.0242 vs. tirzepatide). In regression analyses, the slope of the relationship between change in M value and change in weight was statistically different between semaglutide and tirzepatide (p = 0.0461). These relationships were also assessed using the Matsuda index as the metric of insulin sensitivity, and using change in fat mass as the determinant of change in insulin sensitivity.
    CONCLUSIONS: Improvement in insulin sensitivity was proportional to weight and fat loss, with greater strength of association with tirzepatide. In regression analysis, tirzepatide was associated with greater improvement in insulin sensitivity per unit weight loss than semaglutide. The greater improvement in insulin sensitivity following treatment with tirzepatide was not simply attributable to greater weight or fat loss.
    Keywords:  GIP; GLP‐1; insulin sensitivity; tirzepatide; weight loss
    DOI:  https://doi.org/10.1111/dom.16159
  4. Clin Transl Med. 2025 Jan;15(1): e70166
    PINK1 modulates Prdx2 to reduce lipotoxicity-induced apoptosis and attenuate cardiac dysfunction in heart failure mice with a preserved ejection fraction.
    Hao Zhang, Tianyu Xu, Xiyuan Mei, Qiming Zhao, Qiling Yang, Xianghui Zeng, Zhuang Ma, Haobin Zhou, Qingchun Zeng, Dingli Xu, Hao Ren.
       INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear.
    OBJECTIVE: This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.
    METHODS: In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.
    RESULTS: We determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1-133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.
    CONCLUSION: PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.
    KEY POINTS: Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF. Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate cardiomyocyte apoptosis by modulating the JNK and p38 pathways, thereby alleviating myocardial lipotoxicity and improving HFpEF cardiac function. Our studies offer valuable insights, opening avenues for the development of innovative therapeutic strategies in the prevention and treatment of HFpEF.
    DOI:  https://doi.org/10.1002/ctm2.70166
  5. Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]
    Formation of I2+III2 supercomplex rescues respiratory chain defects.
    Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.
      Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.
    Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
  6. Sci Immunol. 2025 Jan 10. 10(103): eadl4909
    Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
    Cody Elkins, Chengyu Ye, Pulavendran Sivasami, Roy Mulpur, Pamela P Diaz-Saldana, Amy Peng, Miaoer Xu, Yeun-Po Chiang, Samara Moll, Dormarie E Rivera-Rodriguez, Luisa Cervantes-Barragan, Tuoqi Wu, Byron B Au-Yeung, Christopher D Scharer, Mandy L Ford, Haydn Kissick, Chaoran Li.
      Regulatory T cells (Tregs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2hi VAT Treg subsets. Treg-specific deletion of Srebf2, the master regulator of cholesterol homeostasis, selectively reduced ST2hi VAT Tregs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2hi VAT Treg subsets after Srebf2 deletion. Srebf2-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2hi VAT Treg accumulation. However, long-term high-fat diet feeding disrupted VAT Treg cholesterol homeostasis and impaired clonal expansion of the ST2hi subset. Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4909
  7. Diabetes. 2025 Jan 09. pii: db240289. [Epub ahead of print]
    Time-resolved effects of short-term overfeeding on energy balance in mice.
    Pablo Ranea-Robles, Camilla Lund, Charlotte Svendsen, Cláudia Gil, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen.
      To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion. Furthermore, to assess the role of adipose tissue thermogenesis in protecting against overfeeding-induced weight gain, we analyze the expression of genes involved in futile metabolic cycles in response to overfeeding and subject uncoupling protein 1 (UCP1) knockout (KO) mice to intragastric overfeeding. Data from two independent experiments demonstrate that 7 days of 140-150% overfeeding results in substantial weight gain and triggers a potent, sustained decrease in voluntary food intake, which coincides with a gradual return of body weight toward baseline after overfeeding. Intragastric overfeeding triggers an increase in energy expenditure that seems to be adaptive. However, mice lacking UCP1 are not impaired in their ability to defend against overfeeding-induced weight gain. Finally, we show that fecal energy excretion decreases in response to overfeeding, but only during the recovery period, driven primarily by a reduction in fecal output rather than in fecal caloric density. In conclusion, while overfeeding may induce adaptive thermogenesis, the primary protective response to forced weight gain in mice appears to be a potent reduction in food intake.
    DOI:  https://doi.org/10.2337/db24-0289
  8. Cell Mol Life Sci. 2025 Jan 08. 82(1): 39
    The protective effects of liraglutide in reducing lipid droplets accumulation and myocardial fibrosis in diabetic cardiomyopathy.
    Chien-Yin Kuo, Sing-Hua Tsou, Edy Kornelius, Kuei-Chuan Chan, Kai-Wei Chang, Jung-Chi Li, Chien-Ning Huang, Chih-Li Lin.
       BACKGROUND: Diabetes is a primary contributor to diabetic cardiomyopathy (DbCM), which is marked by metabolic imbalances such as elevated blood glucose and lipid levels, leading to significant structural and functional alterations in the myocardium. Elevated free fatty acids (FFAs) and hyperglycemia play critical roles in DbCM development, with FFAs inducing insulin resistance in cardiomyocytes and promoting lipid accumulation, resulting in oxidative stress and fibrosis. Current research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may effectively mitigate DbCM, although an effective treatment for this condition remains elusive, and the precise mechanisms of this protective effect are not fully understood.
    METHODS: In this study, we aimed to replicate diabetic glucolipotoxic conditions by treating differentiated H9c2 cells with high glucose and free fatty acids. Additionally, a diabetic cardiomyopathy model was induced in mice through high-fat diets. Both in vitro and in vivo models were used to investigate the protective effects of liraglutide on cardiomyocytes and elucidate its underlying molecular mechanisms.
    RESULTS: Our findings indicate that liraglutide significantly reduces lipid droplet (LD) formation and myocardial fibrosis, as evidenced by decreased expression of fibrosis markers, including TGF-β1 and collagen types I and III. Liraglutide also enhanced AMP-activated protein kinase (AMPK) activation, which improved mitochondrial function, increased antioxidant gene expression, enhanced insulin signaling, and reduced oxidative stress.
    CONCLUSIONS: These results demonstrate the potential therapeutic role of liraglutide in managing diabetes-related cardiac complications, offering a comprehensive approach to improving cardiac outcomes in patients with diabetes.
    Keywords:  AMP-activated protein kinase (AMPK); Diabetic cardiomyopathy; Fibrosis; Lipid droplet; Liraglutide
    DOI:  https://doi.org/10.1007/s00018-024-05558-9
  9. N Engl J Med. 2025 Jan 09. 392(2): 173-184
    Heart Failure with Preserved Ejection Fraction.
    Antonio Cannata, Theresa A McDonagh.
      
    DOI:  https://doi.org/10.1056/NEJMcp2305181
  10. Nat Cell Biol. 2025 Jan 07.
    Mitochondrial YME1L1 governs unoccupied protein translocase channels.
    Meng-Chieh Hsu, Hiroki Kinefuchi, Linlin Lei, Reika Kikuchi, Koji Yamano, Richard J Youle.
      Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60. While stabilization of the dihydrofolate reductase domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, notably, plugging the channel of translocase of the outer membrane) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 seems to play a crucial role in mitochondrial quality control to counteract precursor stalling in the translocase of the outer membrane complex and unoccupied TIM23 channels.
    DOI:  https://doi.org/10.1038/s41556-024-01571-z
  11. Nat Rev Endocrinol. 2025 Jan 06.
    Enhancing adipose tissue plasticity: progenitor cell roles in metabolic health.
    Simon Lecoutre, Clémentine Rebière, Salwan Maqdasy, Mélanie Lambert, Sébastien Dussaud, Jimon Boniface Abatan, Isabelle Dugail, Emmanuel L Gautier, Karine Clément, Geneviève Marcelin.
      Adipose tissue demonstrates considerable plasticity and heterogeneity, enabling metabolic, cellular and structural adaptations to environmental signals. This adaptability is key for maintaining metabolic homeostasis. Impaired adipose tissue plasticity can lead to abnormal adipose tissue responses to metabolic cues, which contributes to the development of cardiometabolic diseases. In chronic obesity, white adipose tissue undergoes pathological remodelling marked by adipocyte hypertrophy, chronic inflammation and fibrosis, which are linked to local and systemic insulin resistance. Research data suggest that the capacity for healthy or unhealthy white adipose tissue remodelling might depend on the intrinsic diversity of adipose progenitor cells (APCs), which sense and respond to metabolic cues. This Review highlights studies on APCs as key determinants of adipose tissue plasticity, discussing differences between subcutaneous and visceral adipose tissue depots during development, growth and obesity. Modulating APC functions could improve strategies for treating adipose tissue dysfunction and metabolic diseases in obesity.
    DOI:  https://doi.org/10.1038/s41574-024-01071-y
  12. Nat Med. 2025 Jan 06.
    Burdens of type 2 diabetes and cardiovascular disease attributable to sugar-sweetened beverages in 184 countries.
    Global Dietary Database
      The consumption of sugar-sweetened beverages (SSBs) is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). However, an updated and comprehensive assessment of the global burden attributable to SSBs remains scarce. Here we estimated SSB-attributable T2D and CVD burdens across 184 countries in 1990 and 2020 globally, regionally and nationally, incorporating data from the Global Dietary Database, jointly stratified by age, sex, educational attainment and urbanicity. In 2020, 2.2 million (95% uncertainty interval 2.0-2.3) new T2D cases and 1.2 million (95% uncertainty interval 1.1-1.3) new CVD cases were attributable to SSBs worldwide, representing 9.8% and 3.1%, respectively, of all incident cases. Globally, proportional SSB-attributable burdens were higher among men versus women, younger versus older adults, higher- versus lower-educated adults, and adults in urban versus rural areas. By world region, the highest SSB-attributable percentage burdens were in Latin America and the Caribbean (T2D: 24.4%; CVD: 11.3%) and sub-Saharan Africa (T2D: 21.5%; CVD: 10.5%). From 1990 to 2020, the largest proportional increases in SSB-attributable incident T2D and CVD cases were in sub-Saharan Africa (+8.8% and +4.4%, respectively). Our study highlights the countries and subpopulations most affected by cardiometabolic disease associated with SSB consumption, assisting in shaping effective policies and interventions to reduce these burdens globally.
    DOI:  https://doi.org/10.1038/s41591-024-03345-4
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