bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–11–10
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Ca2+ tunneling architecture and function are important for secretion.
  2. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  3. Mitochondrial elongation impairs breast cancer metastasis.
  4. NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing.
  5. Skin senescence-from basic research to clinical practice.
  6. Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation.
  7. Division of labour: mitochondria split to meet energy demands.
  8. Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
  9. Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.
  10. Metabolite signatures of chronological age, aging, survival, and longevity.
  1. J Cell Biol. 2025 Jan 06. pii: e202402107. [Epub ahead of print]224(1):
    Ca2+ tunneling architecture and function are important for secretion.
    Raphael J Courjaret, Larry E Wagner, Rahaf R Ammouri, David I Yule, Khaled Machaca.
      Ca2+ tunneling requires both store-operated Ca2+ entry (SOCE) and Ca2+ release from the endoplasmic reticulum (ER). Tunneling expands the SOCE microdomain through Ca2+ uptake by SERCA into the ER lumen where it diffuses and is released via IP3 receptors. In this study, using high-resolution imaging, we outline the spatial remodeling of the tunneling machinery (IP3R1; SERCA; PMCA; and Ano1 as an effector) relative to STIM1 in response to store depletion. We show that these modulators redistribute to distinct subdomains laterally at the plasma membrane (PM) and axially within the cortical ER. To functionally define the role of Ca2+ tunneling, we engineered a Ca2+ tunneling attenuator (CaTAr) that blocks tunneling without affecting Ca2+ release or SOCE. CaTAr inhibits Cl- secretion in sweat gland cells and reduces sweating in vivo in mice, showing that Ca2+ tunneling is important physiologically. Collectively our findings argue that Ca2+ tunneling is a fundamental Ca2+ signaling modality.
    DOI:  https://doi.org/10.1083/jcb.202402107
  2. 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
  3. Sci Adv. 2024 Nov 08. 10(45): eadm8212
    Mitochondrial elongation impairs breast cancer metastasis.
    Lucía Minarrieta, Matthew G Annis, Yannick Audet-Delage, Hellen Kuasne, Alain Pacis, Catherine St-Louis, Alexander Nowakowski, Marco Biondini, Mireille Khacho, Morag Park, Peter M Siegel, Julie St-Pierre.
      Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm8212
  4. Ageing Res Rev. 2023 Oct 28. pii: S1568-1637(23)00265-9. [Epub ahead of print] 102106
    NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing.
    Yingying Xu, Weihua Xiao.
      More than a century after the discovery of nicotinamide adenine dinucleotide (NAD+), our understanding of the molecule's role in the biology of ageing continues to evolve. As a coenzyme or substrate for many enzymes, NAD+ governs a wide range of biological processes, including energy metabolism, genomic stability, signal transduction, and cell fate. NAD+ deficiency has been recognised as a bona fide hallmark of tissue degeneration, and restoring NAD+ homeostasis helps to rejuvenate multiple mechanisms associated with tissue ageing. The progressive loss of skeletal muscle homeostasis with age is directly associated with high morbidity, disability and mortality. The aetiology of skeletal muscle ageing is complex, involving mitochondrial dysfunction, senescence and stem cell depletion, autophagy defects, chronic cellular stress, intracellular ion overload, immune cell dysfunction, circadian clock disruption, microcirculation disorders, persistent denervation, and gut microbiota dysbiosis. This review focuses on the therapeutic potential of NAD+ restoration to alleviate the above pathological factors and discusses the effects of in vivo administration of different NAD+ boosting strategies on skeletal muscle homeostasis, aiming to provide a reference for combating skeletal muscle ageing.
    Keywords:  NAD(+) boosting; NAD(+) metabolism; Skeletal muscle ageing; Therapies
    DOI:  https://doi.org/10.1016/j.arr.2023.102106
  5. Front Med (Lausanne). 2024 ;11 1484345
    Skin senescence-from basic research to clinical practice.
    Natalia Dorf, Mateusz Maciejczyk.
      The most recognizable implications of tissue aging manifest themselves on the skin. Skin laxity, roughness, pigmentation disorders, age spots, wrinkles, telangiectasia or hair graying are symptoms of physiological aging. Development of the senescent phenotype depends on the interaction between aging cells and remodeling of the skin's extracellular matrix (ECM) that contains collagen and elastic fiber. Aging changes occur due to the combination of both endogenous (gene mutation, cellular metabolism or hormonal agents) and exogenous factors (ultraviolet light, environmental pollutants, and unsuitable diet). However, overproduction of mitochondrial reactive oxygen species (ROS) is a key factor driving cellular senescence. Aging theories have disclosed a range of diverse molecular mechanisms that are associated with cellular senescence of the body. Theories best supported by evidence include protein glycation, oxidative stress, telomere shortening, cell cycle arrest, and a limited number of cell divisions. Accumulation of the ECM damage is suggested to be a key factor in skin aging. Every cell indicates a functional and morphological change that may be used as a biomarker of senescence. Senescence-associated β-galactosidase (SA-β-gal), cell cycle inhibitors (p16INK4a, p21CIP1, p27, p53), DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), senescence-associated heterochromatin foci (SAHF), shortening of telomeres or downregulation of lamina B1 constitute just an example of aging biomarkers known so far. Aging may also be assessed non-invasively through measuring the skin fluorescence of advanced glycation end-products (AGEs). This review summarizes the recent knowledge on the pathogenesis and clinical conditions of skin aging as well as biomarkers of skin senescence.
    Keywords:  aging; biomarkers; senescence; skin; skin aging
    DOI:  https://doi.org/10.3389/fmed.2024.1484345
  6. Cell Commun Signal. 2024 Nov 06. 22(1): 533
    Breast cancer cells utilize T3 to trigger proliferation through cellular Ca2+ modulation.
    Ines Tawfik, Katharina Schlick, Julian Ostaku, Doruntina Bresilla, Sonja Gabrijelčič, Benjamin Gottschalk, Alwin Sokolowski, Ernst Malle, Katarina Kalinova, Martin Hirtl, Corina T Madreiter-Sokolowski.
      High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca2+ handling proteins, thereby boosting mitochondrial Ca2+ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca2+-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca2+ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer.
    Keywords:  Breast cancer; Calcium homeostasis; IP3R3; Mitochondria; Thyroid hormone receptor α; Thyroid hormones
    DOI:  https://doi.org/10.1186/s12964-024-01917-y
  7. Nature. 2024 Nov 06.
    Division of labour: mitochondria split to meet energy demands.
    Lena Pernas.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03469-0
  8. Cell Calcium. 2024 Oct 23. pii: S0143-4160(24)00120-9. [Epub ahead of print]124 102962
    Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
    David G Nicholls.
      In a recent publication, Hernansanz-Agusti̒n et al. propose that a sodium gradient across the inner mitochondrial membrane, generated by a Na+/H+ activity integral to Complex I can account for half of the mitochondrial membrane potential. This conflicts with conventional electrophysiological and chemiosmotic understanding.
    Keywords:  Calcium signaling; Goldman equation; Membrane potential; Mitochondria; Sodium proton exchange
    DOI:  https://doi.org/10.1016/j.ceca.2024.102962
  9. Brain Behav Immun. 2024 Nov 03. pii: S0889-1591(24)00687-1. [Epub ahead of print]
    Acute exercise boosts NAD+ metabolism of human peripheral blood mononuclear cells.
    David Walzik, Niklas Joisten, Alexander Schenk, Sina Trebing, Kirill Schaaf, Alan J Metcalfe, Polyxeni Spiliopoulou, Johanna Hiefner, Adrian McCann, Carsten Watzl, Per Magne Ueland, Sebastian Gehlert, Anna Worthmann, Charles Brenner, Philipp Zimmer.
      Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central electron carriers in biological energy metabolism. Low NAD+ levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD+ levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD+ levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD+ metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD+ metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that - similar to skeletal muscle - NAD+ salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+ salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD+ levels and reduced serum levels of the NAD+ precursor nicotinamide. These results demonstrate that acute exercise triggers NAD+ biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.
    Keywords:  Exercise; Immune cell; Metabolism; NAD(+); Nicotinamide adenine dinucleotide; PBMC
    DOI:  https://doi.org/10.1016/j.bbi.2024.11.004
  10. Cell Rep. 2024 Nov 05. pii: S2211-1247(24)01264-6. [Epub ahead of print]43(11): 114913
    Metabolite signatures of chronological age, aging, survival, and longevity.
    Paola Sebastiani, Stefano Monti, Michael S Lustgarten, Zeyuan Song, Dylan Ellis, Qu Tian, Michaela Schwaiger-Haber, Ethan Stancliffe, Anastasia Leshchyk, Meghan I Short, Andres V Ardisson Korat, Anastasia Gurinovich, Tanya Karagiannis, Mengze Li, Hannah J Lords, Qingyan Xiang, Megan M Marron, Harold Bae, Mary F Feitosa, Mary K Wojczynski, Jeffrey R O'Connell, May E Montasser, Nicole Schupf, Konstantin Arbeev, Anatoliy Yashin, Nicholas Schork, Kaare Christensen, Stacy L Andersen, Luigi Ferrucci, Noa Rappaport, Thomas T Perls, Gary J Patti.
      Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.
    Keywords:  CP: Metabolism; aging; centenarians; longevity; metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114913
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