bims-mimcad 2024-07-07 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024‒07‒07
eight papers selected by
Henver Brunetta, University of Guelph

MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.
Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.
Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.
Bridging lipid metabolism and mitochondrial genome maintenance.
ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.
PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.
GTPBP8 plays a role in mitoribosome formation in human mitochondria.
Comparative Determination of Mitochondrial Biomarkers and Their Relationship With Insulin Resistance in Type 2 Diabetic Patients: An Observational Cross-Sectional Study.

FEBS J. 2024 Jun 30.

MitoNEET preserves muscle insulin sensitivity during iron overload by regulating mitochondrial iron, reactive oxygen species and fission.

Eddie Tam, Khang Nguyen, Hye Kyoung Sung, Gary Sweeney.

  Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron-sulfur domain-containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO-induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p-Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1-dependent mitochondrial fission, mitophagy, FUN14 domain-containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO-induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi-1, prevented IO-induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO-induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission.

Keywords:  insulin resistance; iron overload; mitoNEET; mitochondria; mitochondrial dynamics; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.17214
Mol Metab. 2024 Jul 01. pii: S2212-8778(24)00114-5. [Epub ahead of print] 101983

Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.

Alexis Diaz-Vegas, Kristen C Cooke, Harry B Cutler, Belinda Yau, Stewart W C Masson, Dylan Harney, Oliver K Fuller, Meg Potter, Søren Madsen, Niamh R Craw, Yiju Zhang, Cesar L Moreno, Melkam Kebede, G Gregory Neely, Jacqueline Stöckli, James G Burchfield, David E James.

  Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP. To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance. We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway. These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.

Keywords:  Adipose Tissue; Insulin Resistance; Metabolism; Mitochondria; Peptidases; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101983
Circ Res. 2024 Jul 01.

Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.

Yoshinobu Nakayama, Satoru Kobayashi, Aliya Masihuddin, Syed Amir Abdali, A M Pramodh Bandara Seneviratne, Sachiyo Ishii, Jun Iida, Qiangrong Liang, Jun Yoshioka.

  BACKGROUND: Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.OBJECTIVE: To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac and skeletal myopathy.
METHODS AND RESULTS: High glucose promoted translocation of MondoA into the nucleus, which upregulated Arrdc4 transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of ARRDC4 was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial Arrdc4 expression in multiple types of mouse models of diabetes. We then analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. However, deletion of Arrdc4 augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that Arrdc4-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type (WT) animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression (beyond levels observed during diabetes) using adenoassociated virus suggests that high levels of myocardial ARRDC4 have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the ARRDC4 mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.
CONCLUSIONS: ARRDC4 serves as a regulator of hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.

Keywords:  adaptor protein; diabetic cardiomyopathy; energy metabolism; exercise endurance; health

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323158
J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)01999-9. [Epub ahead of print] 107498

Bridging lipid metabolism and mitochondrial genome maintenance.

Casadora Boone, Samantha C Lewis.

  Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.

Keywords:  Mitochondria; lipid metabolism; lipotoxicity; mitochondrial DNA (mtDNA); mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.jbc.2024.107498
bioRxiv. 2024 Jun 21. pii: 2024.06.21.600099. [Epub ahead of print]

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Ian K Williamson, Janet Pham, Angela Davidian, Radhika Khanna, Benjamin D Gould, Rebecca Salazar, Heidi Vitrac, An Dinh, Evan C Lien, Francisca N de L Vitorino, Joanna M Gongora, Sara A Martinez, Czer S C Lawrence, Evan P Kransdorf, David Leffer, Blake Hanson, Benjamin A Garcia, Matthew G Vander Heiden, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear.Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.
Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate.
Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

DOI: https://doi.org/10.1101/2024.06.21.600099
Nat Metab. 2024 Jul 03.

PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.

Qingzhang Zhu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G Straub, Qian Lin, Shangang Zhao, Chanmin Joung, Zhuzhen Zhang, Dae-Seok Kim, Na Li, Christy M Gliniak, Charlotte Lee, Alberto Cebrian-Serrano, Line Pedersen, Nils Halberg, Ruth Gordillo, Christine M Kusminski, Philipp E Scherer.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

DOI: https://doi.org/10.1038/s42255-024-01078-9
Nat Commun. 2024 Jul 05. 15(1): 5664

GTPBP8 plays a role in mitoribosome formation in human mitochondria.

Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.

Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.

DOI: https://doi.org/10.1038/s41467-024-50011-x
Endocrinol Diabetes Metab. 2024 Jul;7(4): e507

Comparative Determination of Mitochondrial Biomarkers and Their Relationship With Insulin Resistance in Type 2 Diabetic Patients: An Observational Cross-Sectional Study.

Emmanuel K Ofori, Wormenor Dziedzorm, Alfred Buabeng, Francis K Dogodzi, Laurinda X Adusu-Donkor, Segla K Bernard, Seth K Amponsah, Henry Asare-Anane.

  INTRODUCTION: Data suggest malfunctioning mitochondria reduce oxidation and adenosine triphosphate (ATP) production, disrupting insulin signalling. Cytochrome c (CC), acylcarnitine (AC) and citrate synthase (CS) are essential components of the mitochondria machinery and can be used as reliable biomarkers of mitochondrial dysfunction. This study aimed to determine whether mitochondrial biomarkers (AC, CS and CC) are altered in individuals with type 2 diabetes mellitus (T2DM) and to examine the association between these biomarkers and insulin resistance.METHODOLOGY: A cross-sectional observational study that recruited 170 participants (88 with T2DM and 82 without DM) was conducted. Blood samples were collected from the recruits and analysed for levels of fasting glucose (FBG), AC, CS, CC, insulin, total cholesterol, triglycerides (TG), glycated haemoglobin (HbA1c) and magnesium. Blood pressure (BP) and anthropometric characteristics of participants were also taken. Appropriate formulas were used to determine %body fat, body mass index (BMI), waist-to-hip ratio (WHR), the homeostatic model assessment for insulin resistance (HOMA-IR) and insulin sensitivity (HOMA-β).
RESULTS: Patients with T2DM had higher levels of CC, %body fat, FBG, TG, HbA1c, BMI and HOMA-IR than controls (p < 0.05, respectively). Results showed a significant relationship between circulating CC levels versus HOMA-β (r = -0.40, p = 0.001), CS (r = -0.70, p = 0.001) and AC (r = -0.72, p = 0.001) levels in patients with T2DM. The adjusted odds increased in the T2DM patients for VLDL (OR = 6.66, p = 0.002), HbA1c (OR = 6.50, p = 0.001), FPG (OR = 3.17, p = 0.001), TG (OR = 2.36, p = 0.010), being female (OR = 2.09, p = 0.020) and CC (OR = 1.14, p = 0.016).
CONCLUSION: Overall, alterations in mitochondrial biomarkers, measured by AC, CC and CS, were observed in people with T2DM and showed a direct relationship with insulin resistance. These findings are potentially significant in Africa, although additional confirmation from a larger cohort is necessary.

Keywords:  acylcarnitine; citrate synthase; cytochrome c; mitochondria; type 2 diabetes

DOI:  https://doi.org/10.1002/edm2.507