bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–10–13
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.
  2. ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.
  3. CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
  4. Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline.
  5. Senescent cells promote breast cancer cells motility by secreting GM-CSF and bFGF that activate the JNK signaling pathway.
  6. Defining and characterizing neuronal senescence, 'neurescence', as GX arrested cells.
  7. Mapping epidermal and dermal cellular senescence in human skin aging.
  8. CISD2 counteracts the inhibition of ER-mitochondrial calcium transfer by anti-apoptotic BCL-2.
  9. The lysosomal lipid transporter LIMP-2/SCARB2 is part of lysosome-endoplasmic reticulum STARD3-VAPB-dependent contact sites.
  10. Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes.
  11. Organellular imaging in vivo reveals a depletion of endoplasmic reticular calcium during post-ictal cortical spreading depolarization.
  12. Crosstalk between mitochondria-ER contact sites and the apoptotic machinery as a novel health meter.
  13. Calcium signaling in mitochondrial intermembrane space.
  14. Daily briefing: Is this where mitochondria came from?
  1. Cell Calcium. 2024 Oct 05. pii: S0143-4160(24)00116-7. [Epub ahead of print]124 102958
    The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism.
    Cristina Mammucari.
      Mitochondrial Ca2+ plays a positive role in regulating pyruvate dehydrogenase, as well as the TCA cycle enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. This regulation boosts the production of reducing equivalents that fuel the electron transport chain, ultimately driving ATP production. The Mitochondrial Calcium Uniporter (MCU) is the highly selective channel responsible for mitochondrial Ca2+ uptake when local Ca2+ levels reach the threshold for channel activation. In a recent study, LaMoia et al. used an innovative [13C5]glutamine-based metabolic flux analysis method (Q-flux) to measure in vivo hepatic metabolic fluxes in liver-specific MCU-/- mice. Surprisingly, they observed increased flux through isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Metabolic pathways are continuously reorganized in response to intrinsic cellular signals, as well as hormonal and nutritional inputs. Integrating metabolic flux analysis into complex systems can provide deeper insights into how metabolic adaptations occur under different conditions.
    Keywords:  Calcium; Metabolic flux; Mitochondrial calcium uniporter; TCA cycle
    DOI:  https://doi.org/10.1016/j.ceca.2024.102958
  2. Commun Biol. 2024 Oct 10. 7(1): 1294
    ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.
    Giulia Dematteis, Laura Tapella, Claudio Casali, Maria Talmon, Elisa Tonelli, Simone Reano, Adele Ariotti, Emanuela Pessolano, Justyna Malecka, Gabriela Chrostek, Gabrielė Kulkovienė, Danielius Umbrasas, Carla Distasi, Mariagrazia Grilli, Graham Ladds, Nicoletta Filigheddu, Luigia Grazia Fresu, Katsuhiko Mikoshiba, Carlos Matute, Paula Ramos-Gonzalez, Aiste Jekabsone, Tito Calì, Marisa Brini, Marco Biggiogera, Fabio Cavaliere, Riccardo Miggiano, Armando A Genazzani, Dmitry Lim.
      IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.
    DOI:  https://doi.org/10.1038/s42003-024-06933-9
  3. Immunometabolism (Cobham). 2024 Oct;6(4): e00048
    CD38 and the mitochondrial calcium uniporter contribute to age-related hematopoietic stem cell dysfunction.
    Connor S R Jankowski, Thomas Weichhart.
      Hematopoietic stem cells (HSCs) are the multipotent progenitors of all immune cells. During aging, their regenerative capacity decreases for reasons that are not well understood. Recently, Song et al investigated the roles of two metabolic proteins in age-related HSC dysfunction: CD38 (a membrane-bound NADase) and the mitochondrial calcium uniporter that transports calcium into the mitochondrial matrix. They found that the interplay between these proteins is deranged in aged HSCs, contributing to their diminished renewal capacity. These findings implicate compromised nicotinamide adenine dinucleotide metabolism as underlying HSC dysfunction in aging.
    Keywords:  CD38; aging; hematopoiesis; mitochondria; mitochondrial calcium uniporter; nicotinamide adenine dinucleotide metabolism
    DOI:  https://doi.org/10.1097/IN9.0000000000000048
  4. Aging Cell. 2024 Oct 07. e14340
    Senescent cell transplantation into the skin induces age-related peripheral dysfunction and cognitive decline.
    Ana Catarina Franco, Helene Martini, Stella Victorelli, Anthony B Lagnado, Saranya P Wyles, Jennifer L Rowsey, Nicholas Pirius, Seung-Hwa Woo, Daniela G Costa, Selim Chaib, Stefan G Tullius, Tamar Tchkonia, James L Kirkland, Sundeep Khosla, Diana Jurk, Claudia Cavadas, João F Passos.
      Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.
    Keywords:  cellular senescence; cognitive decline; paracrine senescence; skin aging
    DOI:  https://doi.org/10.1111/acel.14340
  5. Cell Commun Signal. 2024 Oct 07. 22(1): 478
    Senescent cells promote breast cancer cells motility by secreting GM-CSF and bFGF that activate the JNK signaling pathway.
    Nan Wang, Yan Fang, Yigong Hou, Dongmei Cheng, Emily V Dressler, Hao Wang, Juan Wang, Guanwen Wang, Yilei Li, Hong Liu, Rong Xiang, Shuang Yang, Peiqing Sun.
       BACKGROUND: Cellular senescence can be induced in mammalian tissues by multiple stimuli, including aging, oncogene activation and loss of tumor suppressor genes, and various types of stresses. While senescence is a tumor suppressing mechanism when induced within premalignant or malignant tumor cells, senescent cells can promote cancer development through increased secretion of growth factors, cytokines, chemokines, extracellular matrix, and degradative enzymes, collectively known as senescence-associated secretory phenotype (SASP). Previous studies indicated that senescent cells, through SASP factors, stimulate tumor cell invasion that is a critical step in cancer cell metastasis.
    METHODS: In the current study, we investigated the effect of senescent cells on the motility of breast cancer cells, which is another key step in cancer cell metastasis. We analyzed the motility of breast cancer cells co-cultured with senescent cells in vitro and metastasis of the breast cancer cells co-injected with senescent cells in orthotopic xenograft models. We also delineated the signaling pathway mediating the effect of senescent cells on cancer cell motility.
    RESULTS: Our results indicate that senescent cells stimulated the migration of breast cancer cells through secretion of GM-CSF and bFGF, which in turn induced activation of the JNK pathway in cancer cells. More importantly, senescent cells promoted breast cancer metastasis, with a minimum effect on the primary tumor growth, in orthotopic xenograft mouse models.
    CONCLUSIONS: These results have revealed an additional mechanism by which senescent cells promote tumor cell metastasis and tumor progression, and will potentially lead to identification of novel targets for cancer therapies that suppress metastasis, the major cause of cancer mortality.
    Keywords:  Breast cancer; GM-CSF; JNK; Metastasis; Migration; Senescence; bFGF
    DOI:  https://doi.org/10.1186/s12964-024-01861-x
  6. Trends Neurosci. 2024 Oct 09. pii: S0166-2236(24)00178-4. [Epub ahead of print]
    Defining and characterizing neuronal senescence, 'neurescence', as GX arrested cells.
    Hannah R Hudson, Markus Riessland, Miranda E Orr.
      Cellular senescence is a cell state characterized by resistance to apoptosis and stable cell cycle arrest. Senescence was first observed in mitotic cells in vitro. Recent evidence from in vivo studies and human tissue indicates that postmitotic cells, including neurons, may also become senescent. The quiescent cell state of neurons and inconsistent descriptions of neuronal senescence across studies, however, have caused confusion in this burgeoning field. We summarize evidence demonstrating that exit from G0 quiescence may protect neurons against apoptosis and predispose them toward senescence. Additionally, we propose the term 'neurescent' for senescent neurons and introduce the cell state, GX, to describe cell cycle arrest achieved by passing through G0 quiescence. Criteria are provided to identify neurescent cells, distinguish them from G0 quiescent neurons, and compare neurescent phenotypes with classic replicative senescence.
    Keywords:  aging; apoptosis; cell cycle; cell stress; neurodegeneration; quiescence
    DOI:  https://doi.org/10.1016/j.tins.2024.09.006
  7. Aging Cell. 2024 Oct 06. e14358
    Mapping epidermal and dermal cellular senescence in human skin aging.
    Grace T Yu, Clarisse Ganier, David B Allison, Tamara Tchkonia, Sundeep Khosla, James L Kirkland, Magnus D Lynch, Saranya P Wyles.
      Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae.
    Keywords:  cellular senescence; dermis; epidermis; single‐cell gene expression analysis; skin aging; skin pathology; spatial analysis
    DOI:  https://doi.org/10.1111/acel.14358
  8. Biochim Biophys Acta Mol Cell Res. 2024 Oct 04. pii: S0167-4889(24)00200-3. [Epub ahead of print]1872(1): 119857
    CISD2 counteracts the inhibition of ER-mitochondrial calcium transfer by anti-apoptotic BCL-2.
    Jens Loncke, Ian de Ridder, Justin Kale, Larry Wagner, Allen Kaasik, Jan B Parys, Martijn Kerkhofs, David W Andrews, David Yule, Tim Vervliet, Geert Bultynck.
      CISD2, a 2Fe2S cluster domain-containing protein, is implicated in Wolfram syndrome type 2, longevity and cancer. CISD2 is part of a ternary complex with IP3 receptors (IP3Rs) and anti-apoptotic BCL-2 proteins and enhances BCL-2's anti-autophagic function. Here, we examined how CISD2 impacted the function of BCL-2 in apoptosis and in controlling IP3R-mediated Ca2+ signaling. Using purified proteins, we found a direct interaction between the cytosolic region of CISD2 and BCL-2's BH4 domain with a submicromolar affinity. At the functional level, the cytosolic region of CISD2, as a purified protein, did not affect the ability of BCL-2 to inhibit BAX-pore formation. In a cellular context, loss of CISD2 did not impede the suppression of apoptosis by BCL-2. Also, in Ca2+-signaling assays, absence of CISD2 did not affect the inhibition of IP3R-mediated Ca2+ release by BCL-2. Combined, these experiments indicate that CISD2 is not essential for BCL-2 function in apoptosis and cytosolic Ca2+ signaling. Instead, CISD2 overexpression enhanced BCL-2-mediated suppression of cytosolic IP3R-mediated Ca2+ release. However, consistent with the presence of CISD2 and BCL-2 at mitochondria-associated ER membranes (MAMs), the most striking effect was observed at the level of ER-mitochondrial Ca2+ transfer. While BCL-2 overexpression inhibited ER-mitochondrial Ca2+ transfer, overexpression of CISD2 together with BCL-2 abrogated the effect of BCL-2. The underlying mechanism is linked to ER-mitochondrial contact sites, since BCL-2 reduced ER-mitochondrial contact sites while co-expression of CISD2 together with BCL-2 abolished this effect. These findings reveal a unique interplay between BCL-2 and CISD2 at Ca2+-signaling nanodomains between ER and mitochondria.
    Keywords:  BCL-2; Calcium signaling; IP(3) receptor; Iron‑sulfur cluster proteins; Naf-1
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119857
  9. J Cell Sci. 2024 Oct 07. pii: jcs.261810. [Epub ahead of print]
    The lysosomal lipid transporter LIMP-2/SCARB2 is part of lysosome-endoplasmic reticulum STARD3-VAPB-dependent contact sites.
    Sönke Rudnik, Saskia Heybrock, Etienne Coyaud, Zizhen Xu, Dante Neculai, Brian Raught, Viola Oorschot, Cecilia Heus, Judith Klumperman, Paul Saftig.
      SCARB2/LIMP-2 is an abundant lysosomal membrane protein. Previous studies have shown LIMP-2 functions as a virus receptor, a chaperone for lysosomal enzyme targeting, and a lipid transporter. The large luminal domain of LIMP-2 contains a hydrophobic tunnel that enables transport of phospholipids, sphingosine and cholesterol from the lysosomal lumen to the membrane. The question about the fate of the lipids after LIMP-2-mediated transport is largely unexplored. To elucidate whether LIMP-2 is part of contact sites between lysosomes and the endoplasmic reticulum (ER), we performed a proximity-based interaction screen. This revealed that LIMP-2 interacts with the endosomal protein STARD3 and the ER-resident protein VAPB. Using imaging and co-immunoprecipitation, we demonstrated colocalization and physical interaction between LIMP-2 and these proteins. Moreover, we found that interaction of LIMP-2 with VAPB required the presence of STARD3. Our findings suggest that LIMP-2 is part of ER-lysosome contact sites, possibly facilitating cholesterol transport from the lysosomal to the ER membrane. This suggests a novel mechanism for inter-organelle communication and lipid trafficking mediated by LIMP-2.
    Keywords:  Endoplasmic reticulum; LIMP-2; Lysosome; Membrane contact sites; SCARB2; STARD3; VAPB
    DOI:  https://doi.org/10.1242/jcs.261810
  10. Stem Cell Res Ther. 2024 Oct 10. 15(1): 359
    Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes.
    Rebecca M Irwin, Matthew A Thomas, Megan J Fahey, María D Mayán, James W Smyth, Michelle L Delco.
       BACKGROUND: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes.
    METHODS: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer.
    RESULTS: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes.
    CONCLUSIONS: Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.
    Keywords:  Arthritis; Cx43; GJA1; GJA1-20k; Gap junctions; MSCs; Osteoarthritis; Regenerative medicine
    DOI:  https://doi.org/10.1186/s13287-024-03932-9
  11. bioRxiv. 2024 Sep 24. pii: 2024.09.21.614252. [Epub ahead of print]
    Organellular imaging in vivo reveals a depletion of endoplasmic reticular calcium during post-ictal cortical spreading depolarization.
    Matthew A Stern, Eric R Cole, Claire-Anne Gutekunst, Jenny J Yang, Ken Berglund, Robert E Gross.
      During cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.
    DOI:  https://doi.org/10.1101/2024.09.21.614252
  12. Trends Cell Biol. 2024 Oct 07. pii: S0962-8924(24)00185-5. [Epub ahead of print]
    Crosstalk between mitochondria-ER contact sites and the apoptotic machinery as a novel health meter.
    Alvaro Larrañaga-SanMiguel, Nora Bengoa-Vergniory, Hector Flores-Romero.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) function as transient signaling platforms that regulate essential cellular functions. MERCS are enriched in specific proteins and lipids that connect mitochondria and the ER together and modulate their activities. Dysregulation of MERCS is associated with several human pathologies including Alzheimer's disease (AD), Parkinson's disease (PD), and cancer. BCL-2 family proteins can locate at MERCS and control essential cellular functions such as calcium signaling and autophagy in addition to their role in mitochondrial apoptosis. Moreover, the BCL-2-mediated apoptotic machinery was recently found to trigger cGAS-STING pathway activation and a proinflammatory response, a recognized hallmark of these diseases that requires mitochondria-ER interplay. This review underscores the pivotal role of MERCS in regulating essential cellular functions, focusing on their crosstalk with BCL-2 family proteins, and discusses how their dysregulation is linked to disease.
    Keywords:  MAMs; MERCS; apoptosis; cancer; inflammation; neurodegeneration
    DOI:  https://doi.org/10.1016/j.tcb.2024.08.007
  13. Biochem Soc Trans. 2024 Oct 11. pii: BST20240319. [Epub ahead of print]
    Calcium signaling in mitochondrial intermembrane space.
    Shanikumar Goyani, Shatakshi Shukla, Pooja Jadiya, Dhanendra Tomar.
      The mitochondrial intermembrane space (IMS) is a highly protected compartment, second only to the matrix. It is a crucial bridge, coordinating mitochondrial activities with cellular processes such as metabolites, protein, lipid, and ion exchange. This regulation influences signaling pathways for metabolic activities and cellular homeostasis. The IMS harbors various proteins critical for initiating apoptotic cascades and regulating reactive oxygen species production by controlling the respiratory chain. Calcium (Ca2+), a key intracellular secondary messenger, enter the mitochondrial matrix via the IMS, regulating mitochondrial bioenergetics, ATP production, modulating cell death pathways. IMS acts as a regulatory site for Ca2+ entry due to the presence of different Ca2+ sensors such as MICUs, solute carriers (SLCs); ion exchangers (LETM1/SCaMCs); S100A1, mitochondrial glycerol-3-phosphate dehydrogenase, and EFHD1, each with unique Ca2+ binding motifs and spatial localizations. This review primarily emphasizes the role of these IMS-localized Ca2+ sensors concerning their spatial localization, mechanism, and molecular functions. Additionally, we discuss how these sensors contribute to the progression and pathogenesis of various human health conditions and diseases.
    Keywords:  Ca2+ sensors; LETM1; MICU; SCaMs; SLC25A12/13; mitochondrial intermembrane space
    DOI:  https://doi.org/10.1042/BST20240319
  14. Nature. 2024 Oct 04.
    Daily briefing: Is this where mitochondria came from?
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-03280-x
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