bims-mimead Biomed News
on Mitochondrial metabolism in ageing and metabolic disease
Issue of 2024–10–27
nine papers selected by
Rachel M. Handy, University of Guelph
  1. Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
  2. Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
  3. Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.
  4. Nuclear release of eIF1 restricts start-codon selection during mitosis.
  5. Metabolic Bariatric Surgery in the Era of GLP-1 Receptor Agonists for Obesity Management.
  6. Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation.
  7. Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.
  8. Cyclophilin D plays a critical role in the survival of senescent cells.
  9. In-depth proteomics and Phosphoproteomics reveal biomarkers and molecular pathways of chronic intermittent hypoxia in mice.
  1. Physiol Rep. 2024 Oct;12(20): e70088
    Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
    Mona Esbjörnsson, Håkan C Rundqvist, Barbara Norman, Ted Österlund, Eric Rullman, Jens Bülow, Eva Jansson.
      The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30-s all-out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial-related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early-stage inhibition of the mitochondria, potentially as a protective mechanism against SIT-induced oxidative stress.
    Keywords:  biopsy; high intensity; microarray analysis; skeletal muscle; sprint interval exercise; subcutaneous white adipose tissue; transcriptome
    DOI:  https://doi.org/10.14814/phy2.70088
  2. Nat Commun. 2024 Oct 21. 15(1): 9063
    Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.
    Cristiane Dos Santos, Amanda Cambraia, Shristi Shrestha, Melanie Cutler, Matthew Cottam, Guy Perkins, Varda Lev-Ram, Birbickram Roy, Christopher Acree, Keun-Young Kim, Thomas Deerinck, Danielle Dean, Jean Philippe Cartailler, Patrick E MacDonald, Martin Hetzer, Mark Ellisman, Rafael Arrojo E Drigo.
      Caloric restriction (CR) can extend the organism life- and health-span by improving glucose homeostasis. How CR affects the structure-function of pancreatic beta cells remains unknown. We used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis reveal that CR activates transcription factors important for beta cell identity and homeostasis, while imaging metabolomics demonstrates that beta cells upon CR are more energetically competent. In fact, high-resolution microscopy show that CR reduces beta cell mitophagy to increase mitochondria mass and the potential for ATP generation. However, CR beta cells have impaired adaptive proliferation in response to high fat diet feeding. Finally, we show that long-term CR delays the onset of beta cell aging hallmarks and promotes cell longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cell structure-function during aging and diabetes.
    DOI:  https://doi.org/10.1038/s41467-024-53127-2
  3. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.
    Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sarah L Amour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils Faergeman, Andreas M Fritzen, Bente Kiens.
      Several health beneficial effects are associated with intake of medium-chain triacylglycerol (MCT), however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity - and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after eight days intake compared to intake of energy-matched triacylglycerol consisting of long-chain fatty acids (LCT) using a randomized cross-over design in lean individuals (n=8) and individuals with obesity (n=8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate, while lowering blood glucose levels over five hours. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after eight days of daily supplementation. Lipidomic plasma analysis in lean individuals (n=4) showed that a part of the ingested MCT bypasses the liver and entered the systemic circulation as medium-chain fatty acids (MCFA). The findings suggest that MCFA, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.
    Keywords:  Medium-chain fatty acids; Metabolism; ketone bodies; lipid metabolism
    DOI:  https://doi.org/10.1152/ajpendo.00234.2024
  4. Nature. 2024 Oct 23.
    Nuclear release of eIF1 restricts start-codon selection during mitosis.
    Jimmy Ly, Kehui Xiang, Kuan-Chung Su, Gunter B Sissoko, David P Bartel, Iain M Cheeseman.
      Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.
    DOI:  https://doi.org/10.1038/s41586-024-08088-3
  5. JAMA Netw Open. 2024 Oct 01. 7(10): e2441380
    Metabolic Bariatric Surgery in the Era of GLP-1 Receptor Agonists for Obesity Management.
    Kevin Lin, Ateev Mehrotra, Thomas C Tsai.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2024.41380
  6. Cell Signal. 2024 Oct 18. pii: S0898-6568(24)00453-4. [Epub ahead of print]124 111478
    Sirt1-mediated deacetylation of PGC-1α alleviated hepatic steatosis in type 2 diabetes mellitus via improving mitochondrial fatty acid oxidation.
    Jiale Pang, Longxiang Yin, Wenjie Jiang, Haiyan Wang, Qian Cheng, Zhenzhou Jiang, Yanjuan Cao, Xia Zhu, Baojing Li, Sitong Qian, Xiaoxing Yin, Tao Wang, Qian Lu, Tingting Yang.
      Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (Sirt1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated Sirt1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased Sirt1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated Sirt1 inactivated PGC-1α by inhibiting its deacetylation, while activating Sirt1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of Sirt1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating Sirt1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.
    Keywords:  Mitochondrial FAO; PGC-1α deacetylation; Sirt1 activation; T2DM-associated FLD
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111478
  7. Cell Metab. 2024 Oct 15. pii: S1550-4131(24)00376-0. [Epub ahead of print]
    Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.
    Kenichi Sakamoto, Mary A Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, Donald A Morgan, Kamal Rahmouni, Gary J Schwartz, Azeddine Tahiri, Christoph Buettner.
      The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.
    Keywords:  adipose tissue dysfunction; adipose tissue lipolysis; diabetes; insulin resistance; liver steatosis; metabolic disease; metabolic inflammation; norepinephrine; obesity; sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.012
  8. EMBO J. 2024 Oct 24.
    Cyclophilin D plays a critical role in the survival of senescent cells.
    Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.
      Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
    Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering
    DOI:  https://doi.org/10.1038/s44318-024-00259-2
  9. J Proteomics. 2024 Oct 19. pii: S1874-3919(24)00266-5. [Epub ahead of print] 105334
    In-depth proteomics and Phosphoproteomics reveal biomarkers and molecular pathways of chronic intermittent hypoxia in mice.
    Huanhuan Fang, Ye Zhang, Liangming Zhu, Jinzhao Lyu, Qiang Li.
      Obstructive sleep apnea (OSA) syndrome is characterized by Chronic Intermittent Hypoxia (CIH). In this study, we employed Data-independent acquisition (DIA) Mass Spectrometry to conduct comprehensive proteomic and phosphoproteomic profiling of a murine model subjected to Chronic Intermittent Hypoxia (CIH), a model we had previously established. Utilizing three CIH and three normal control genioglossus samples, we gathered valuable insights into the molecular alterations associated with CIH. Our analyses identified a total of 4576 protein groups and 13,867 phosphosites. Differential analysis of the proteomic data highlighted a significant upregulation of Ras signaling (Egf, Ngf, and Fyb1) and calcium signaling (Tnn, Thbs4, and Ppp2r2d) in CIH samples, contrasting with a notable decrease in oxidative phosphorylation (Atp5mf, Atp5me, and Atp5mg). Additionally, we observed a substantial increase in the phosphorylation of PI3K-AKT signaling (Ptk2_Y861, Mapk3_T203, and Eif4b_S230) and HIF-1 signaling (Gapdh_S208, Eno3_T229, and Camk2b_T382) in CIH samples. These findings prompted a deeper investigation into the association of the characterized proteins and phosphoproteins with Obstructive Sleep Apnea (OSA). The comprehensive profiling revealed molecular signatures that may serve as valuable insights into the pathophysiology of chronic intermittent hypoxia and its link to obstructive sleep apnea. Our observations provide a foundation for future research endeavors, offering potential avenues for advancing our understanding and treatment strategies for these conditions. SIGNIFICANCE: The significance of this study lies in its comprehensive exploration of the molecular mechanisms underpinning Chronic Intermittent Hypoxia (CIH), a key feature of Obstructive Sleep Apnea (OSA). By employing Data-independent acquisition (DIA) Mass Spectrometry, this research provides an in-depth proteomic and phosphoproteomic analysis, uncovering critical signaling pathways and molecular alterations associated with CIH. The identification of significant changes in Ras and calcium signaling pathways, along with increased phosphorylation in PI3K-AKT and HIF-1 signaling, offers novel insights into the pathophysiological processes involved in CIH and OSA. These findings not only enhance our understanding of the molecular basis of OSA but also pave the way for the development of targeted therapeutic strategies, ultimately contributing to better management and treatment of OSA and related conditions.
    Keywords:  Chronic intermittent hypoxia; Obstructive sleep apnea; Phosphoproteome; Proteome
    DOI:  https://doi.org/10.1016/j.jprot.2024.105334
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