bims-cesemi 2024-11-03 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–11–03
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development.
ER stress as a sentinel mechanism for ER Ca2+ homeostasis.
Aging, senescence, and cutaneous wound healing-a complex relationship.
Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia.
Ca+2 and Nε-lysine acetylation regulate the CALR-ATG9A interaction in the lumen of the endoplasmic reticulum.
Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?
Oxidative stress and cell senescence as drivers of ageing: Chicken and egg.
Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals.

PLoS Biol. 2024 Oct 28. 22(10): e3002854

MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development.

Alison Robert, David Crottès, Jérôme Bourgeais, Naig Gueguen, Arnaud Chevrollier, Jean-François Dumas, Stéphane Servais, Isabelle Domingo, Stéphanie Chadet, Julien Sobilo, Olivier Hérault, Thierry Lecomte, Christophe Vandier, William Raoul, Maxime Guéguinou.

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and invasion using in vitro and in vivo models of human colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming.

DOI: https://doi.org/10.1371/journal.pbio.3002854
Cell Calcium. 2024 Oct 18. pii: S0143-4160(24)00119-2. [Epub ahead of print]124 102961

ER stress as a sentinel mechanism for ER Ca2+ homeostasis.

Tadashi Makio, Junsheng Chen, Thomas Simmen.

  Endoplasmic reticulum (ER) stress is triggered upon the interference with oxidative protein folding that aims to produce fully folded, disulfide-bonded and glycosylated proteins, which are then competent to exit the ER. Many of the enzymes catalyzing this process require the binding of Ca2+ ions, including the chaperones BiP/GRP78, calnexin and calreticulin. The induction of ER stress with a variety of drugs interferes with chaperone Ca2+ binding, increases cytosolic Ca2+through the opening of ER Ca2+ channels, and activates store-operated Ca2+ entry (SOCE). Posttranslational modifications (PTMs) of the ER Ca2+ handling proteins through ER stress-dependent phosphorylation or oxidation control these mechanisms, as demonstrated in the case of the sarco/endoplasmic reticulum ATPase (SERCA), inositol 1,4,5 trisphosphate receptors (IP3Rs) or stromal interaction molecule 1 (STIM1). Their aim is to restore ER Ca2+ homeostasis but also to increase Ca2+ transfer from the ER to mitochondria during ER stress. This latter function boosts ER bioenergetics, but also triggers apoptosis if ER Ca2+ signaling persists. ER Ca2+ toolkit oxidative modifications upon ER stress can occur within the ER lumen or in the adjacent cytosol. Enzymes involved in this redox control include ER oxidoreductin 1 (ERO1) or the thioredoxin-family protein disulfide isomerases (PDI) and ERp57. A tight, but adaptive connection between ER Ca2+ content, ER stress and mitochondrial readouts allows for the proper functioning of many tissues, including skeletal muscle, the liver, and the pancreas, where ER stress either maintains or compromises their function, depending on its extent and context. Upon mutation of key regulators of ER Ca2+ signaling, diseases such as muscular defects (e.g., from mutated selenoprotein N, SEPN1/SELENON), or diabetes (e.g., from mutated PERK) are the result.

Keywords:  Endoplasmic reticulum (ER); Mitochondria; Mutation; Rare Disease

DOI:  https://doi.org/10.1016/j.ceca.2024.102961
Front Immunol. 2024 ;15 1429716

Aging, senescence, and cutaneous wound healing-a complex relationship.

Steven O'Reilly, Ewa Markiewicz, Olusola C Idowu.

  Cutaneous wound healing is a complex multi-step process that is highly controlled, ensuring efficient repair to damaged tissue and restoring tissue architecture. Multiple cell types play a critical role in wound healing, and perturbations in this can lead to non-healing wounds or scarring and fibrosis. Thus, the process is tightly regulated and controlled. Cellular senescence is defined as irreversible cell cycle arrest and is associated with various phenotypic changes and metabolic alterations and coupled to a secretory program. Its role in wound healing, at least in the acute setting, appears to help promote appropriate mechanisms leading to the complete restoration of tissue architecture. Opposing this is the role of senescence in chronic wounds where it can lead to either chronic non-healing wounds or fibrosis. Given the two opposing outcomes of wound healing in either acute or chronic settings, this has led to disparate views on the role of senescence in wound healing. This review aims to consolidate knowledge on the role of senescence and aging in wound healing, examining the nuances of the roles in the acute or chronic settings, and attempts to evaluate the modulation of this to promote efficient wound healing.

Keywords:  SASP (senescence-associated secretory phenotype); inflammation; senescence; skin wound; wound healing

DOI:  https://doi.org/10.3389/fimmu.2024.1429716
Cell Metab. 2024 Oct 19. pii: S1550-4131(24)00396-6. [Epub ahead of print]

Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.

Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich.

  Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.

Keywords:  ALKBH5; MDH2; PDGFRβ; alpha-ketoglutarate; cancer stem cell; epitranscriptomics; glioblastoma; m6A; malate-aspartate shuttle; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.09.014
Cancer Sci. 2024 Oct 31.

Noncanonical TCA cycle fosters canonical TCA cycle and mitochondrial integrity in acute myeloid leukemia.

Atsushi Watanabe, Chartsiam Tipgomut, Haruhito Totani, Kentaro Yoshimura, Tomohiko Iwano, Hamed Bashiri, Lee Hui Chua, Chong Yang, Toshio Suda.

  Cancer cells rely on mitochondrial oxidative phosphorylation (OXPHOS) and the noncanonical tricarboxylic acid (TCA) cycle. In this paper, we shed light on the vital role played by the noncanonical TCA cycle in a host-side concession to mitochondria, especially in highly energy-demanding malignant tumor cells. Inhibition of ATP-citrate lyase (ACLY), a key enzyme in the noncanonical TCA cycle, induced apoptosis by increasing reactive oxygen species levels and DNA damage while reducing mitochondrial membrane potential. The mitochondrial membrane citrate transporter inhibitor, CTPI2, synergistically enhanced these effects. ACLY inhibition reduced cytosolic citrate levels and CTPI2 lowered ACLY activity, suggesting that the noncanonical TCA cycle is sustained by a positive feedback mechanism. These inhibitions impaired ATP production, particularly through OXPHOS. Metabolomic analysis of mitochondrial and cytosolic fractions revealed reduced levels of glutathione pathway-related and TCA cycle-related metabolite, except fumarate, in mitochondria following noncanonical TCA cycle inhibition. Despite the efficient energy supply to the cell by mitochondria, this symbiosis poses challenges related to reactive oxygen species and mitochondrial maintenance. In conclusion, the noncanonical TCA cycle is indispensable for the canonical TCA cycle and mitochondrial integrity, contributing to mitochondrial domestication.

Keywords:  ATP‐citrate lyase; antimetabolites; apoptosis; cancer metabolism; cell lines; hematopoietic organ; mitochondria; noncanonical TCA cycle; others; reactive oxygen species

DOI:  https://doi.org/10.1111/cas.16347
Sci Rep. 2024 10 26. 14(1): 25532

Ca+2 and Nε-lysine acetylation regulate the CALR-ATG9A interaction in the lumen of the endoplasmic reticulum.

Megan M Braun, Brendan K Sheehan, Samantha L Shapiro, Yun Ding, C Dustin Rubinstein, Brent P Lehman, Luigi Puglielli.

  The acetylation of autophagy protein 9 A (ATG9A) in the lumen of the endoplasmic reticulum (ER) by ATase1 and ATase2 regulates the induction of reticulophagy. Analysis of the ER-specific ATG9A interactome identified calreticulin (CALR), an ER luminal Ca+2-binding chaperone, as key for ATG9A activity. Specifically, if acetylated, ATG9A is sequestered by CALR and prevented from engaging FAM134B and SEC62. Under this condition, ATG9A is unable to activate the autophagy core machinery. In contrast, when non-acetylated, ATG9A is released by CALR and able to engage FAM134B and SEC62. In this study, we report that Ca+2 dynamics across the ER membrane regulate the ATG9A-CALR interaction as well as the ability of ATG9A to trigger reticulophagy. We show that the Ca+2-binding sites situated on the C-domain of CALR are essential for the ATG9A-CALR interaction. Finally, we show that K359 and K363 on ATG9A can influence the ATG9A-CALR interaction. Collectively, our results disclose a previously unidentified aspect of the complex mechanisms that regulate ATG9A activity. They also offer a possible area of intersection between Ca+2 metabolism, acetyl-CoA metabolism, and ER proteostasis.

Keywords:  ATG9A; Calcium; Calreticulin; Lysine acetylation; Proteostasis; Reticulophagy

DOI:  https://doi.org/10.1038/s41598-024-76854-4
Int J Mol Sci. 2024 Oct 11. pii: 10932. [Epub ahead of print]25(20):

Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?

Thomas Gustafsson, Brun Ulfhake.

  As we age, we lose muscle strength and power, a condition commonly referred to as sarcopenia (ICD-10-CM code (M62.84)). The prevalence of sarcopenia is about 5-10% of the elderly population, resulting in varying degrees of disability. In this review we emphasise that sarcopenia does not occur suddenly. It is an aging-induced deterioration that occurs over time and is only recognised as a disease when it manifests clinically in the 6th-7th decade of life. Evidence from animal studies, elite athletes and longitudinal population studies all confirms that the underlying process has been ongoing for decades once sarcopenia has manifested. We present hypotheses about the mechanism(s) underlying this process and their supporting evidence. We briefly review various proposals to impede sarcopenia, including cell therapy, reducing senescent cells and their secretome, utilising targets revealed by the skeletal muscle secretome, and muscle innervation. We conclude that although there are potential candidates and ongoing preclinical and clinical trials with drug treatments, the only evidence-based intervention today for humans is exercise. We present different exercise programmes and discuss to what extent the interindividual susceptibility to developing sarcopenia is due to our genetic predisposition or lifestyle factors.

Keywords:  ageing; dynapenia; motor unit; muscle fibre atrophy; senescence

DOI:  https://doi.org/10.3390/ijms252010932
Ageing Res Rev. 2024 Oct 23. pii: S1568-1637(24)00376-3. [Epub ahead of print]102 102558

Oxidative stress and cell senescence as drivers of ageing: Chicken and egg.

Thomas von Zglinicki.

  Oxidative stress and cell senescence are both important drivers of ageing and age-associated disease and disability. In vitro, they are closely interconnected in a chicken-and-egg relationship: Not only is oxidative stress an important cause of cell senescence, but senescent cells are also sources of oxidative stress, obscuring cause-effect relationships during the ageing process. We hypothesize that cell senescence is a significant cause of tissue and systemic oxidative stress during ageing. This review aims to critically summarize the available evidence for this hypothesis. After summarizing the cellular feedback mechanisms that make oxidative stress an integral part of the senescent phenotype, it critically reviews the existing evidence for a role of senescent cells as causes of oxidative stress during mammalian ageing in vivo, focussing on results from intervention experiments. It is concluded that while the available data are in agreement with this hypothesis, they are still too scarce to support a robust conclusion.

Keywords:  Ageing; Cell senescence; Oxidative stress

DOI:  https://doi.org/10.1016/j.arr.2024.102558
Sci Adv. 2024 Nov;10(44): eadp7022

Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals.

Zheng Wang, Yinglu Chen, Hui Fang, Kai Xiao, Ziping Wu, Xiaochun Xie, Jie Liu, Fangman Chen, Yi He, Liang Wang, Chao Yang, Renjun Pei, Dan Shao.

Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)-induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux-orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8+ T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy.

DOI: https://doi.org/10.1126/sciadv.adp7022