bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–08–25
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
  2. MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
  3. Ca2+ puffs underlie adhesion-triggered Ca2+ microdomains in T cells.
  4. Inner membrane turns inside out to exit mitochondrial organelles.
  5. Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration.
  6. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
  7. Damage-Induced Senescent Immune Cells Regulate Regeneration of the Zebrafish Retina.
  8. Targeting miR-29 mitigates skeletal senescence and bolsters therapeutic potential of mesenchymal stromal cells.
  9. Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
  10. Interplay of mitochondrial calcium signalling and reactive oxygen species production in the brain.
  11. Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
  1. iScience. 2024 Aug 16. 27(8): 110510
    BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
    Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K F Aguettaz, Mauricio Castro-Sepulveda, Dorian V Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, Francesca Amati.
      The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca2+ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca2+ release and mitochondrial Ca2+ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca2+ signaling, contributes to proper skeletal muscle function.
    Keywords:  cell biology; pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2024.110510
  2. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2402491121
    MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.
    Prottoy Hasan, Elena Berezhnaya, Macarena Rodríguez-Prados, David Weaver, Carmen Bekeova, Benjamin Cartes-Saavedra, Erin Birch, Andreas M Beyer, Janine H Santos, Erin L Seifert, John W Elrod, György Hajnóczky.
      Activating Ca2+-sensitive enzymes of oxidative metabolism while preventing calcium overload that leads to mitochondrial and cellular injury requires dynamic control of mitochondrial Ca2+ uptake. This is ensured by the mitochondrial calcium uptake (MICU)1/2 proteins that gate the pore of the mitochondrial calcium uniporter (mtCU). MICU1 is relatively sparse in the heart, and recent studies claimed the mammalian heart lacks MICU1 gating of mtCU. However, genetic models have not been tested. We find that MICU1 is present in a complex with MCU in nonfailing human hearts. Furthermore, using murine genetic models and pharmacology, we show that MICU1 and MICU2 control cardiac mitochondrial Ca2+ influx, and that MICU1 deletion alters cardiomyocyte mitochondrial calcium signaling and energy metabolism. MICU1 loss causes substantial compensatory changes in the mtCU composition and abundance, increased turnover of essential MCU regulator (EMRE) early on and, later, of MCU, that limit mitochondrial Ca2+ uptake and allow cell survival. Thus, both the primary consequences of MICU1 loss and the ensuing robust compensation highlight MICU1's relevance in the beating heart.
    Keywords:  MICU1; MICU2; calcium; cardiomyocyte; mitochondrial calcium uniporter gating
    DOI:  https://doi.org/10.1073/pnas.2402491121
  3. Biochim Biophys Acta Mol Cell Res. 2024 Aug 14. pii: S0167-4889(24)00151-4. [Epub ahead of print] 119808
    Ca2+ puffs underlie adhesion-triggered Ca2+ microdomains in T cells.
    Roberto Ornelas-Guevara, Björn-Philipp Diercks, Andreas H Guse, Geneviève Dupont.
      Ca2+ signalling is pivotal in T cell activation, an essential process in adaptive immune responses. Key to this activation are Ca2+ microdomains, which are transient increases in cytosolic Ca2+ concentration occurring within narrow regions between the endoplasmic reticulum (ER) and the plasma membrane (PM), lasting a few tens of milliseconds. Adhesion Dependent Ca2+ Microdomains (ADCM) rely on store-operated Ca2+ entry (SOCE) via the ORAI/STIM system. The nanometric scale at which these microdomains form poses challenges for direct experimental observation. Following the previous work of Gil et al. [1], which introduced a three-dimensional model of the ER-PM junction, this study combines a detailed description of the Ca2+ fluxes at the junction with stochastic dynamics of a cluster of D-myo-inositol 1,4,5 trisphosphate receptors (IP3R) located in the ER surrounding the junction. Because the consideration of Ca2+ release through the IP3R calls for the simulation of a portion of the cytoplasm considerably larger than the junction, our study also investigates the spatial distribution of PMCAs, revealing their likely localization outside the ER-PM junction. Simulations indicate that Ca2+ puffs implying the opening of 2-6 IP3Rs create ADCMs by provoking local depletions of ER Ca2+ stimulating Ca2+ entry through the ORAI1 channels. Such conditions allow the reproduction of the amplitude, duration and spatial extent of the observed ADCMs. By integrating advanced computational techniques with insights from experimental studies, our approach provides valuable information on the mechanisms governing early Ca2+ signalling in T cell activation, paving the way for a deeper understanding of immune responses.
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119808
  4. Nature. 2024 Aug;632(8027): 987-988
    Inner membrane turns inside out to exit mitochondrial organelles.
    David Pla-Martín, Andreas S Reichert.
      
    Keywords:  Biochemistry; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02528-w
  5. Invest Ophthalmol Vis Sci. 2024 Aug 01. 65(10): 29
    Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration.
    Ryo Terao, Brian S Sohn, Taku Yamamoto, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Shinobu Yamaguchi, Mitsukuni Yoshida, Rajendra S Apte.
       Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors.
    Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina.
    Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch's membrane thickening.
    Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.
    DOI:  https://doi.org/10.1167/iovs.65.10.29
  6. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00287-0. [Epub ahead of print]
    Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation.
    Traci E LaMoia, Brandon T Hubbard, Mateus T Guerra, Ali Nasiri, Ikki Sakuma, Mario Kahn, Dongyan Zhang, Russell P Goodman, Michael H Nathanson, Yasemin Sancak, Mark Perelis, Vamsi K Mootha, Gerald I Shulman.
      To examine the roles of mitochondrial calcium Ca2+ ([Ca2+]mt) and cytosolic Ca2+ ([Ca2+]cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca2+]mt and increased [Ca2+]cyt content. Despite decreased [Ca2+]mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [14C16]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca2+]cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca2+]mt and reveal a key role for [Ca2+]cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
    Keywords:  CAMKII; Q-Flux; calcium; fat oxidation; glucose oxidation; isocitrate dehydrogenase flux; metabolic dysfunction-associated steatotic liver disease; mitochondria; mitochondrial calcium uniporter; succinate dehydrogenase flux; tricarboxylic acid cycle; type 2 diabetes; α-ketoglutarate dehydrogenase flux
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.016
  7. Aging Biol. 2024 ;pii: e20240021. [Epub ahead of print]2
    Damage-Induced Senescent Immune Cells Regulate Regeneration of the Zebrafish Retina.
    Gregory J Konar, Zachary Flickinger, Shivani Sharma, Kyle T Vallone, Charles E Lyon, Claire Doshier, Audrey Lingan, William Lyon, James G Patton.
      Zebrafish spontaneously regenerate their retinas in response to damage through the action of Müller glia (MG). Even though MG are conserved in higher vertebrates, the capacity to regenerate retinal damage is lost. Recent work has focused on the regulation of inflammation during tissue regeneration, with temporal roles for macrophages and microglia. Senescent cells that have withdrawn from the cell cycle have mostly been implicated in aging but are still metabolically active, releasing a variety of signaling molecules as part of the senescence-associated secretory phenotype. Here, we discover that in response to retinal damage, a subset of cells expressing markers of microglia/macrophages also express markers of senescence. These cells display a temporal pattern of appearance and clearance during retina regeneration. Premature removal of senescent cells by senolytic treatment led to a decrease in proliferation and incomplete repair of the ganglion cell layer after N-methyl-D-aspartate damage. Our results demonstrate a role for modulation of senescent cell responses to balance inflammation, regeneration, plasticity, and repair as opposed to fibrosis and scarring.
    DOI:  https://doi.org/10.59368/agingbio.20240021
  8. Cell Rep Med. 2024 Aug 20. pii: S2666-3791(24)00379-3. [Epub ahead of print]5(8): 101665
    Targeting miR-29 mitigates skeletal senescence and bolsters therapeutic potential of mesenchymal stromal cells.
    Zhen Ding, Guixing Ma, Bo Zhou, Siyuan Cheng, Wanze Tang, Yingying Han, Litong Chen, Wei Pang, Yangshan Chen, Dazhi Yang, Huiling Cao.
      Mesenchymal stromal cell (MSC) senescence is a key factor in skeletal aging, affecting the potential of MSC applications. Identifying targets to prevent MSC and skeletal senescence is crucial. Here, we report increased miR-29 expression in bone tissues of aged mice, osteoporotic patients, and senescent MSCs. Genetic overexpression of miR-29 in Prx1-positive MSCs significantly accelerates skeletal senescence, reducing cortical bone thickness and trabecular bone mass, while increasing femur cross-sectional area, bone marrow adiposity, p53, and senescence-associated secretory phenotype (SASP) levels. Mechanistically, miR-29 promotes senescence by upregulating p53 via targeting Kindlin-2 mRNA. miR-29 knockdown in BMSCs impedes skeletal senescence, enhances bone mass, and accelerates calvarial defect regeneration, also reducing lipopolysaccharide (LPS)-induced organ injuries and mortality. Thus, our findings underscore miR-29 as a promising therapeutic target for senescence-related skeletal diseases and acute inflammation-induced organ damage.
    Keywords:  Kindlin-2; MSC therapy; aging; bone; bone repair; miR-29; osteoporosis; p53; skeletal senescence
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101665
  9. Sci Adv. 2024 Aug 23. 10(34): eado8549
    Succinate dehydrogenase-complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema.
    Joseph Balnis, Ankita Tufts, Emily L Jackson, Lisa A Drake, Diane V Singer, David Lacomis, Chun Geun Lee, Jack A Elias, Jason D Doles, L James Maher, Annie Jen, Joshua J Coon, David Jourd'heuil, Harold A Singer, Catherine E Vincent, Ariel Jaitovich.
      Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.
    DOI:  https://doi.org/10.1126/sciadv.ado8549
  10. Biochem Soc Trans. 2024 Aug 22. pii: BST20240261. [Epub ahead of print]
    Interplay of mitochondrial calcium signalling and reactive oxygen species production in the brain.
    Plamena R Angelova, Andrey Y Abramov.
      Intracellular communication and regulation in brain cells is controlled by the ubiquitous Ca2+ and by redox signalling. Both of these independent signalling systems regulate most of the processes in cells including the cell surviving mechanism or cell death. In physiology Ca2+ can regulate and trigger reactive oxygen species (ROS) production by various enzymes and in mitochondria but ROS could also transmit redox signal to calcium levels via modification of calcium channels or phospholipase activity. Changes in calcium or redox signalling could lead to severe pathology resulting in excitotoxicity or oxidative stress. Interaction of the calcium and ROS is essential to trigger opening of mitochondrial permeability transition pore - the initial step of apoptosis, Ca2+ and ROS-induced oxidative stress involved in necrosis and ferroptosis. Here we review the role of redox signalling and Ca2+ in cytosol and mitochondria in the physiology of brain cells - neurons and astrocytes and how this integration can lead to pathology, including ischaemia injury and neurodegeneration.
    Keywords:  calcium; glial cell; mitochondria; mitochondrial permeability transition pores; neuron; reactive oxygen species
    DOI:  https://doi.org/10.1042/BST20240261
  11. Nature. 2024 Aug 21.
    Lysosomes drive the piecemeal removal of mitochondrial inner membrane.
    Akriti Prashar, Claudio Bussi, Antony Fearns, Mariana I Capurro, Xiaodong Gao, Hiromi Sesaki, Maximiliano G Gutierrez, Nicola L Jones.
      Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41586-024-07835-w
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