bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024‒06‒16
nine papers selected by
Henver Brunetta, University of Guelph
  1. The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.
  2. Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
  3. The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
  4. Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH dependent manner.
  5. Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.
  6. Metabolic inflexibility promotes mitochondrial health during liver regeneration.
  7. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
  8. Depletion of SASP senescent cardiomyocytes with senolytic drugs confers therapeutic effects in doxorubicin-related cardiotoxicity.
  9. Association of Sarcopenia and Oxygen Uptake Efficiency Slope in Male Patients With Heart Failure.
  1. Circ Res. 2024 Jun 14.
    The Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.
    Wenjuan Wang, Ermin Li, Jianqiu Zou, Chen Qu, Juan Ayala, Yuan Wen, Md Sadikul Islam, Neal L Weintraub, David J Fulton, Qiangrong Liang, Jiliang Zhou, Jinbao Liu, Jie Li, Yi Sun, Huabo Su.
      BACKGROUND: Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. Apart from Parkin, little is known about additional Ub (ubiquitin) ligases that mediate mitochondrial ubiquitination and turnover, particularly in highly metabolically active organs such as the heart.METHODS: In this study, we have combined in silico analysis and biochemical assay to identify CRL (cullin-RING ligase) 5 as a mitochondrial Ub ligase. We generated cardiomyocytes and mice lacking RBX2 (RING-box protein 2; also known as SAG [sensitive to apoptosis gene]), a catalytic subunit of CRL5, to understand the effects of RBX2 depletion on mitochondrial ubiquitination, mitophagy, and cardiac function. We also performed proteomics analysis and RNA-sequencing analysis to define the impact of loss of RBX2 on the proteome and transcriptome.
    RESULTS: RBX2 and CUL (cullin) 5, 2 core components of CRL5, localize to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, increased cardiomyocyte cell death, and has a global impact on the mitochondrial proteome. In vivo, deletion of the Rbx2 gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to the rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. The action of RBX2 in mitochondria is not dependent on Parkin, and Parkin gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 in mitochondria.
    CONCLUSIONS: These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that regulates mitophagy and cardiac homeostasis in a Parkin-independent, PINK1-dependent manner.
    Keywords:  heart failure; mitochondria; mitophagy; protein kinases; ubiquitination
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324285
  2. Cell Mol Life Sci. 2024 Jun 10. 81(1): 254
    Pyruvate kinase M2 sustains cardiac mitochondrial quality surveillance in septic cardiomyopathy by regulating prohibitin 2 abundance via S91 phosphorylation.
    Yingzhen Du, Jialei Li, Zhe Dai, Yuxin Chen, Yao Zhao, Xiaoman Liu, Tian Xia, Pingjun Zhu, Yijin Wang.
      The endogenous mitochondrial quality control (MQC) system serves to protect mitochondria against cellular stressors. Although mitochondrial dysfunction contributes to cardiac damage during many pathological conditions, the regulatory signals influencing MQC disruption during septic cardiomyopathy (SC) remain unclear. This study aimed to investigate the involvement of pyruvate kinase M2 (PKM2) and prohibitin 2 (PHB2) interaction followed by MQC impairment in the pathogenesis of SC. We utilized LPS-induced SC models in PKM2 transgenic (PKM2TG) mice, PHB2S91D-knockin mice, and PKM2-overexpressing HL-1 cardiomyocytes. After LPS-induced SC, cardiac PKM2 expression was significantly downregulated in wild-type mice, whereas PKM2 overexpression in vivo sustained heart function, suppressed myocardial inflammation, and attenuated cardiomyocyte death. PKM2 overexpression relieved sepsis-related mitochondrial damage via MQC normalization, evidenced by balanced mitochondrial fission/fusion, activated mitophagy, restored mitochondrial biogenesis, and inhibited mitochondrial unfolded protein response. Docking simulations, co-IP, and domain deletion mutant protein transfection experiments showed that PKM2 phosphorylates PHB2 at Ser91, preventing LPS-mediated PHB2 degradation. Additionally, the A domain of PKM2 and the PHB domain of PHB2 are required for PKM2-PHB2 binding and PHB2 phosphorylation. After LPS exposure, expression of a phosphorylation-defective PHB2S91A mutant negated the protective effects of PKM2 overexpression. Moreover, knockin mice expressing a phosphorylation-mimetic PHB2S91D mutant showed improved heart function, reduced inflammation, and preserved mitochondrial function following sepsis induction. Abundant PKM2 expression is a prerequisite to sustain PKM2-PHB2 interaction which is a key element for preservation of PHB2 phosphorylation and MQC, presenting novel interventive targets for the treatment of septic cardiomyopathy.
    Keywords:  MQC; Mitochondria; PHB2; PKM2; Septic cardiomyopathy
    DOI:  https://doi.org/10.1007/s00018-024-05253-9
  3. Nat Commun. 2024 Jun 08. 15(1): 4915
    The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
    Joan Serrano, Jordan Boyd, Ian S Brown, Carter Mason, Kathleen R Smith, Katalin Karolyi, Santosh K Maurya, Nishita N Meshram, Vanida Serna, Grace M Link, Stephen J Gardell, George A Kyriazis.
      The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.
    DOI:  https://doi.org/10.1038/s41467-024-49100-8
  4. J Endocrinol. 2024 Jun 01. pii: JOE-24-0032. [Epub ahead of print]
    Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH dependent manner.
    Jordan Sf Chan, Amanda A Greenwell, Christina T Saed, Magnus J Stenlund, Indiresh A Mangra-Bala, Seyed Amirhossein Tabatabaei Dakhilli, Kunyan Yang, Sally R Ferrari, Farah Eaton, Keshav Gopal, John R Ussher.
      Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting-enzyme of glucose oxidation. Male Pdha1CM-/- mice and their myosin heavy chain-α Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10-weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week-4. All mice were randomized to treatment with either vehicle control (VC) or liraglutide (30 μg/kg) twice daily during the final 2.5-weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1CM-/- mice with T2D, in the absence of weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1CM-/- mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e'/a' and E/e' ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1CM-/- mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.
    DOI:  https://doi.org/10.1530/JOE-24-0032
  5. Cell Rep. 2024 Jun 09. pii: S2211-1247(24)00665-X. [Epub ahead of print]43(6): 114337
    Endogenous p53 inhibitor TIRR dissociates systemic metabolic health from oncogenic activity.
    Eva Tsaousidou, Jędrzej Chrzanowski, Pascal Drané, Grace Y Lee, Nadine Bahour, Zeqiu Branden Wang, Shijun Deng, Zhe Cao, Kaimeng Huang, Yizhou He, Mateusz Kaminski, Dominika Michalek, Ekin Güney, Kalindi Parmar, Wojciech Fendler, Dipanjan Chowdhury, Gökhan S Hotamışlıgil.
      It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metabolism; cancer mouse model of p53 activation; cancer protection; in vivo physiology in cancer; mevalonate pathway suppression; obesity and cancer; overweight and cancer; p53 activation; p53 derepression; p53 inhibitor; type 2 diabetes and cancer
    DOI:  https://doi.org/10.1016/j.celrep.2024.114337
  6. Science. 2024 Jun 14. 384(6701): eadj4301
    Metabolic inflexibility promotes mitochondrial health during liver regeneration.
    Xun Wang, Cameron J Menezes, Yuemeng Jia, Yi Xiao, Siva Sai Krishna Venigalla, Feng Cai, Meng-Hsiung Hsieh, Wen Gu, Liming Du, Jessica Sudderth, Dohun Kim, Spencer D Shelton, Claire B Llamas, Yu-Hsuan Lin, Min Zhu, Salma Merchant, Divya Bezwada, Sherwin Kelekar, Lauren G Zacharias, Thomas P Mathews, Gerta Hoxhaj, R Max Wynn, Uttam K Tambar, Ralph J DeBerardinis, Hao Zhu, Prashant Mishra.
      Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial β-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.
    DOI:  https://doi.org/10.1126/science.adj4301
  7. Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]
    MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
    Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.
      Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
    Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2024.05.017
  8. FEBS J. 2024 Jun 10.
    Depletion of SASP senescent cardiomyocytes with senolytic drugs confers therapeutic effects in doxorubicin-related cardiotoxicity.
    Wenzheng Xia, Hanbin Chen, Han Yang, Liaoxiang Zhu, Congying Xie, Meng Hou.
      Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing these senescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H2A.X was used to assess the SASP in the Dox-treated heart. To explore the molecular mechanisms involved, the Bcl-2 inhibitor ABT-199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl-2, although treatment of mice with ABT-199 selectively eliminated SASP senescent cardiomyocytes involved in Dox-induced cardiotoxicity, thus leading to partial alleviation of Dox-induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox-dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox-induced cardiac injury.
    Keywords:  SASP; cell communication; chemotherapy related cardiotoxicity; exosome; senolytic drugs
    DOI:  https://doi.org/10.1111/febs.17164
  9. J Cardiopulm Rehabil Prev. 2024 Jun 07.
    Association of Sarcopenia and Oxygen Uptake Efficiency Slope in Male Patients With Heart Failure.
    Henrique Nunes Bispo, Eduardo Rondon, Marcelo Rodrigues Dos Santos, Francis Ribeiro de Souza, Marcel José Andrade da Costa, Rosa Maria Rodrigues Pereira, Carlos Eduardo Negrão, Brian P Carson, Maria-Janieire de Nazaré Nunes Alves, Guilherme Wesley Peixoto da Fonseca.
      PURPOSE: Sarcopenia, the loss of muscle mass and function, is a common comorbidity in patients with heart failure (HF). The skeletal muscle modulates the respiratory response during exercise. However, whether ventilatory behavior is affected by sarcopenia is still unknown.METHODS: We enrolled 169 male patients with HF. Muscle strength was measured by a handgrip dynamometer. Body composition was measured with dual-energy X-ray absorptiometry. Sarcopenia was defined by handgrip strength <27 kg and appendicular lean mass divided by height squared (ALM/height2) <7.0 kg/m2. Oxygen uptake efficiency slope (OUES), ventilation (VE), oxygen uptake (VO2), and carbon dioxide output (VCO2) were measured by a cardiopulmonary exercise test.
    RESULTS: Sarcopenia was identified in 29 patients (17%). At the first ventilatory threshold, VE/VO2 (36.9 ± 5.9 vs 32.7 ± 6.5; P = .003) and VE/VCO2 (39.8 ± 7.2 vs 35.3 ± 6.9; P = .004) were higher in patients with sarcopenia compared to those without sarcopenia. At the exercise peak, compared to patients with sarcopenia, sarcopenic patients had lower OUES (1186 ± 295 vs 1634 ± 564; P < .001), relative VO2 (16.2 ± 5.0 vs 19.5 ± 6.5 mL/kg/min; P = .011), and VE (47.3 ± 10.1 vs 63.0 ± 18.2 L/min; P < .001), while VE/VCO2 (42.9 ± 8.9 vs 38.7 ± 8.4; P = .025) was increased. OUES was positively correlated with ALM/height2 (r = 0.36; P < .0001) and handgrip strength (r = 0.31; P < .001). Hemoglobin (OR = 1.149; 95% CI, 0.842-1.570; P = .038), ALM/height2 (OR = 2.166; 95% CI, 1.338-3.504; P = .002), and VO2peak (OR = 1.377; 95% CI, 1.218-1.557; P < .001) were independently associated with OUES adjusted by cofounders.
    CONCLUSIONS: Our results suggest that sarcopenia is related to impaired ventilatory response during exercise in patients with HF.
    DOI:  https://doi.org/10.1097/HCR.0000000000000872
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