bims-imseme 2023-08-27 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023‒08‒27
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Glutarate regulates T cell metabolism and anti-tumour immunity.
T cell control of inflammaging.
PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.
Fatty acids support the fitness and functionality of tumor resident CD8+ T cells by maintaining SCML4 expression.
Group 1 metabotropic glutamate receptor expression defines a T cell memory population during chronic Toxoplasma infection that enhances IFN-gamma and perforin production in the CNS.
Deciphering the decline of metabolic elasticity in aging and obesity.
Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells.
Glutarate tunes T cell fate.
Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.
Combination therapy of HIF1α inhibitors and Treg depletion strengthen the anti-tumor immunity in mice.
Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors.
Mass Cytometry as a Tool for Investigating Senescence in Multiple Model Systems.
β2-Adrenergic Receptor Mediated Inhibition of T Cell Function and Its Implications for CAR-T Cell Therapy.
Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.
Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.
Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.
Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism.
Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.

Nat Metab. 2023 Aug 21.

Glutarate regulates T cell metabolism and anti-tumour immunity.

Eleanor Minogue, Pedro P Cunha, Brennan J Wadsworth, Guinevere L Grice, Shiv K Sah-Teli, Rob Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Velica, Laura Barbieri, Craig E Wheelock, Peppi Koivunen, James A Nathan, Iosifina P Foskolou, Randall S Johnson.

T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.

DOI: https://doi.org/10.1038/s42255-023-00855-2
Semin Immunol. 2023 Aug 21. pii: S1044-5323(23)00109-4. [Epub ahead of print]70 101818

T cell control of inflammaging.

Irina Shchukina, Pavla Bohacova, Maxim N Artyomov.

T cells are a critical component of the immune system, found in abundance in blood, secondary lymphoid organs, and peripheral tissues. As individuals age, T cells are particularly susceptible to changes, making them one of the most affected immune subsets. These changes can have significant implications for age-related dysregulations, including the development of low-grade inflammation - a hallmark of aging known as inflammaging. In this review, we first present age-related changes in the functionality of the T cell compartment, including dysregulation of cytokine and chemokine production and cytotoxicity. Next, we discuss how these changes can contribute to the development and maintenance of inflammaging. Furthermore, we will summarize the mechanisms through which age-related changes in T cells may drive abnormal physiological outcomes.

DOI: https://doi.org/10.1016/j.smim.2023.101818
Sci Immunol. 2023 Aug 04. 8(86): eadg0539

PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.

Amanda L Gill, Peter H Wang, Judong Lee, William H Hudson, Satomi Ando, Koichi Araki, Yinghong Hu, Andreas Wieland, Sejin Im, Autumn Gavora, Christopher B Medina, Gordon J Freeman, Masao Hashimoto, Steven L Reiner, Rafi Ahmed.

PD-1+TCF-1+ stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases. To investigate this, we used the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. Treatment of chronically infected mice with either αPD-1 or αPD-L1 antibody not only increased effector cell differentiation from the virus-specific stem-like CD8 T cells but also increased their proliferation so their numbers were maintained. The increased self-renewal of LCMV-specific stem-like CD8 T cells was mTOR dependent. We used microscopy to understand the division of these progenitor cells and found that after PD-1 blockade, an individual dividing cell could give rise to a differentiated TCF-1- daughter cell alongside a self-renewing TCF-1+ sister cell. This asymmetric division helped to preserve the number of stem-like cells. Moreover, we found that the PD-1+TCF-1+ stem-like CD8 T cells retained their transcriptional program and their in vivo functionality in terms of responding to viral infection and to repeat PD-1 blockade. Together, our results demonstrate that PD-1 blockade does not deplete the stem-like population despite increasing effector differentiation. These findings have implications for PD-1-directed immunotherapy in humans.

DOI: https://doi.org/10.1126/sciimmunol.adg0539
Cancer Res. 2023 Aug 23. pii: CAN-23-0287. [Epub ahead of print]

Fatty acids support the fitness and functionality of tumor resident CD8+ T cells by maintaining SCML4 expression.

Maoxiao Feng, Xiaoyan Liu, Xiaodong Hao, Yidan Ren, Guoying Dong, Jie Tian, Yuli Wang, Lutao Du, Chuanxin Wang, Yunshan Wang.

CD8+ tissue-resident memory T (Trm) cells and tumor-infiltrating lymphocytes (TILs) regulate tumor immunity and immune surveillance. Characterization of Trm cells and TILs could help identify potential strategies to boost antitumor immunity. Here, we found that the transcription factor SCML4 was required for the progression and polyfunctionality of Trm cells and was associated with a better prognosis in patients with cancer. Moreover, SCML4 maintained multiple functions of TILs. Increased expression of SCML4 in CD8+ cells significantly reduced the growth of multiple types of tumors in mice, while deletion of SCML4 reduced antitumor immunity and promotes CD8+ T-cell exhaustion. Mechanistically, SCML4 recruited the HBO1-BRPF2-ING4 complex to reprogram the expression of T-cell-specific genes, thereby enhancing the survival and effector functions of Trm cells and TILs. SCML4 expression was promoted by fatty acid metabolism through mTOR-IRF4-PRDM1 signaling, and fatty acid metabolism induced epigenetic modifications that promoted tissue-resident and multifunctional gene expression in Trm cells and TILs. SCML4 increased the therapeutic effect of anti-PD-1 treatment by elevating the expression of effector molecules in TILs and inhibiting the apoptosis of TILs, which could be further enhanced by adding an inhibitor of H3K14ac deacetylation. These results provide a mechanistic perspective of functional regulation of tumor-localized Trm cells and TILs and identify an important activation target for tumor immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0287
Brain Behav Immun. 2023 Aug 19. pii: S0889-1591(23)00239-8. [Epub ahead of print]

Group 1 metabotropic glutamate receptor expression defines a T cell memory population during chronic Toxoplasma infection that enhances IFN-gamma and perforin production in the CNS.

Edward A Vizcarra, Arzu Ulu, Tyler A Landrith, Xinru Qiu, Adam Godzik, Emma H Wilson.

  Within the brain, a pro-inflammatory response is essential to prevent clinical disease due to Toxoplasma gondii reactivation. Infection in the immunocompromised leads to lethal Toxoplasmic encephalitis while in the immunocompetent, there is persistent low-grade inflammation which is devoid of clinical symptoms. This signifies that there is a well-balanced and regulated inflammatory response to T. gondii in the brain. T cells are the dominant immune cells that prevent clinical disease, and this is mediated through the secretion of effector molecules such as perforins and IFN-γ. The presence of cognate antigen, the expression of survival cytokines, and the alteration of the epigenetic landscape drive the development of memory T cells. However, specific extrinsic signals that promote the formation and maintenance of memory T cells within tissue are poorly understood. During chronic infection, there is an increase in extracellular glutamate that, due to its function as an excitatory neurotransmitter, is normally tightly controlled in the CNS. Here we demonstrate that CD8+ T cells from the T. gondii-infected brain parenchyma are enriched for metabotropic glutamate receptors (mGluR's). Characterization studies determined that mGluR+ expression by CD8+ T cells defines a distinct memory population at the transcriptional and protein level. Finally, using receptor antagonists and agonists we demonstrate mGluR signaling is required for optimal CD8+ T cell production of the effector cytokine IFNγ. This work suggests that glutamate is an important environmental signal of inflammation that promotes T cell function. Understanding glutamate's influence on T cells in the brain can provide insights into the mechanisms that govern protective immunity against CNS-infiltrating pathogens and neuroinflammation.

Keywords:  CD8 T cells; Neuroimmunology; Toxoplasma; memory T cells; metabotropic glutamate receptors; single cell RNA sequencing

DOI:  https://doi.org/10.1016/j.bbi.2023.08.015
Cell Metab. 2023 Aug 18. pii: S1550-4131(23)00296-6. [Epub ahead of print]

Deciphering the decline of metabolic elasticity in aging and obesity.

Qiuzhong Zhou, Lexiang Yu, Joshua R Cook, Li Qiang, Lei Sun.

  Organisms must adapt to fluctuating nutrient availability to maintain energy homeostasis. Here, we term the capacity for such adaptation and restoration "metabolic elasticity" and model it through ad libitum-fasting-refeeding cycles. Metabolic elasticity is achieved by coordinate versatility in gene expression, which we call "gene elasticity." We have developed the gene elasticity score as a systematic method to quantify the elasticity of the transcriptome across metabolically active tissues in mice and non-human primates. Genes involved in lipid and carbohydrate metabolism show high gene elasticity, and their elasticity declines with age, particularly with PPARγ dysregulation in adipose tissue. Synchronizing PPARγ activity with nutrient conditions through feeding-timed agonism optimizes their metabolic benefits and safety. We further broaden the conceptual scope of metabolic and gene elasticity to dietary challenges, revealing declines in diet-induced obesity similar to those in aging. Altogether, our findings provide a dynamic perspective on the dysmetabolic consequences of aging and obesity.

Keywords:  adipocyte; adipose tissue; aging; gene elasticity; liver; metabolic decline; metabolic elasticity; muscle; nutrient challenge; obesity

DOI:  https://doi.org/10.1016/j.cmet.2023.08.001
Sci Immunol. 2023 Aug 04. 8(86): eadg0878

Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells.

Etienne Humblin, Isabel Korpas, Jiahua Lu, Dan Filipescu, Verena van der Heide, Simon Goldstein, Abishek Vaidya, Alessandra Soares-Schanoski, Beatrice Casati, Myvizhi E Selvan, Zeynep H Gümüş, Andreas Wieland, Mauro Corrado, Leona Cohen-Gould, Emily Bernstein, Dirk Homann, Jerry Chipuk, Alice O Kamphorst.

During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.

DOI: https://doi.org/10.1126/sciimmunol.adg0878
Nat Metab. 2023 Aug 21.

Glutarate tunes T cell fate.

Francisco Yanqui-Rivera, Christiane A Opitz.

DOI: https://doi.org/10.1038/s42255-023-00878-9
Cells. 2023 Aug 10. pii: 2034. [Epub ahead of print]12(16):

Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection.

Carey L Shive, Corinne M Kowal, Alexandra F Desotelle, Ynez Nguyen, Sarah Carbone, Lenche Kostadinova, Perica Davitkov, Megan O'Mara, Alexandra Reihs, Hinnah Siddiqui, Brigid M Wilson, Donald D Anthony.

  Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.

Keywords:  3-10 HCV; EndoCab; FABP; LBP; T cell exhaustion; inflammation; liver disease; transient elastography

DOI:  https://doi.org/10.3390/cells12162034
Eur J Immunol. 2023 Aug 24. e2250182

Combination therapy of HIF1α inhibitors and Treg depletion strengthen the anti-tumor immunity in mice.

Ping Wei, Wei Kou, Farooq Riaz, Kaimin Zhang, Juan Fu, Fan Pan.

  Hypoxia-inducible factor 1 alpha (HIF1α), under hypoxic conditions, is known to play an oxygen sensor stabilizing role by exerting context- and cell-dependent stimulatory and inhibitory functions in immune cells. Nevertheless, how HIF1α regulates T cell differentiation and functions in tumor settings has not been elucidated. Herein, we demonstrated that T cell-specific deletion of HIF1α improves the inflammatory potential and memory phenotype of CD8+ T cells. We validated that T cell-specific HIF1α ablation reduced the B16 melanomas development with the indication of ameliorated anti-tumor immune response with enhanced IFN-γ+ CD8+ T cells despite the increase in the Foxp3+ regulatory T cell population. This was further verified by treating tumor-bearing mice and purified T cells with a HIF1α inhibitor. Results indicated that HIF1α inhibitor also recapitulates HIF1α ablation effects by declining tumor growth and enhancing the memory and inflammatory potential of CD8+ T cells. Furthermore, a combination of Treg inhibitors with HIF1α inhibitors can substantially reduce tumor size. Collectively, these findings highlight the notable roles of HIF1α in distinct CD8+ T cell subsets. This study suggests the significant implications for enhancing the potential of T cell-based anti-tumor immunity by combining HIF1α and Tregs inhibitors. This article is protected by copyright. All rights reserved.

Keywords:  CD8+ T cells; Foxp3; hypoxia-inducible factor 1 (HIF1α); regulatory T cells; tumor immunity

DOI:  https://doi.org/10.1002/eji.202250182
Nat Commun. 2023 Aug 24. 14(1): 5146

Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors.

Nils-Petter Rudqvist, Maud Charpentier, Claire Lhuillier, Erik Wennerberg, Sheila Spada, Caroline Sheridan, Xi Kathy Zhou, Tuo Zhang, Silvia C Formenti, Jennifer S Sims, Alicia Alonso, Sandra Demaria.

Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.

DOI: https://doi.org/10.1038/s41467-023-40844-3
Cells. 2023 Aug 11. pii: 2045. [Epub ahead of print]12(16):

Mass Cytometry as a Tool for Investigating Senescence in Multiple Model Systems.

Amina Abdul-Aziz, Raymond D Devine, Justin M Lyberger, Hsiaochi Chang, Amy Kovacs, James R Lerma, Andrew M Rogers, John C Byrd, Erin Hertlein, Gregory K Behbehani.

  Cellular senescence is a durable cell cycle arrest as a result of the finite proliferative capacity of cells. Senescence responds to both intrinsic and extrinsic cellular stresses, such as aging, mitochondrial dysfunction, irradiation, and chemotherapy. Here, we report on the use of mass cytometry (MC) to analyze multiple model systems and demonstrate MC as a platform for senescence analysis at the single-cell level. We demonstrate changes to p16 expression, cell cycling fraction, and histone tail modifications in several established senescent model systems and using isolated human T cells. In bone marrow mesenchymal stromal cells (BMSCs), we show increased p16 expression with subsequent passage as well as a reduction in cycling cells and open chromatin marks. In WI-38 cells, we demonstrate increased p16 expression with both culture-induced senescence and oxidative stress-induced senescence (OSIS). We also use Wanderlust, a trajectory analysis tool, to demonstrate how p16 expression changes with histone tail modifications and cell cycle proteins. Finally, we demonstrate that repetitive stimulation of human T cells with CD3/CD28 beads induces an exhausted phenotype with increased p16 expression. This p16-expressing population exhibited higher expression of exhaustion markers such as EOMES and TOX. This work demonstrates that MC is a useful platform for studying senescence at a single-cell protein level, and is capable of measuring multiple markers of senescence at once with high confidence, thereby improving our understanding of senescent pathways.

Keywords:  aging; cell cycle; immunology; mass cytometry; senescence

DOI:  https://doi.org/10.3390/cells12162045
Int J Mol Sci. 2023 Aug 16. pii: 12837. [Epub ahead of print]24(16):

β2-Adrenergic Receptor Mediated Inhibition of T Cell Function and Its Implications for CAR-T Cell Therapy.

Muhammad Asad Farooq, Iqra Ajmal, Xinhui Hui, Yiran Chen, Yaojun Ren, Wenzheng Jiang.

  The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu.

Keywords:  CAR-T therapy; immunosuppression; immunotherapy; tumor microenvironment; β2-adrenergic receptor

DOI:  https://doi.org/10.3390/ijms241612837
PLoS Comput Biol. 2023 Aug 24. 19(8): e1011425

Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.

Jonathan W Cody, Amy L Ellis-Connell, Shelby L O'Connor, Elsje Pienaar.

Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes.

DOI: https://doi.org/10.1371/journal.pcbi.1011425
Aging Cell. 2023 Aug 23. e13954

Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.

Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.

  The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).

Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects

DOI:  https://doi.org/10.1111/acel.13954
Bioessays. 2023 Aug 21. e2300076

The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.

Joshua Ratliffe, Tetsushi Kataura, Elsje G Otten, Viktor I Korolchuk.

  Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age-related diseases associated with impaired autophagy and oxidative stress.

Keywords:  ageing; aggrephagy; autophagy; mitophagy; neurodegeneration; oxidative stress; selective autophagy receptors

DOI:  https://doi.org/10.1002/bies.202300076
Pharmaceuticals (Basel). 2023 Aug 10. pii: 1134. [Epub ahead of print]16(8):

Nicotinamide Riboside Improves Stemness of Human Adipose-Derived Stem Cells and Inhibits Terminal Adipocyte Differentiation.

Somaiah Chinnapaka, Hamid Malekzadeh, Zayaan Tirmizi, José A Arellano, Asim Ejaz.

  Adipose tissue plays a crucial role in maintaining metabolic homeostasis by serving as a storage site for excess fat and protecting other organs from the detrimental effects of lipotoxicity. However, the aging process is accompanied by a redistribution of fat, characterized by a decrease in insulin-sensitive subcutaneous adipose depot and an increase in insulin-resistant visceral adipose depot. This age-related alteration in adipose tissue distribution has implications for metabolic health. Adipose-derived stem cells (ASCs) play a vital role in the regeneration of adipose tissue. However, aging negatively impacts the stemness and regenerative potential of ASCs. The accumulation of oxidative stress and mitochondrial dysfunction-associated cellular damage contributes to the decline in stemness observed in aged ASCs. Nicotinamide adenine dinucleotide (NAD+) is a crucial metabolite that is involved in maintaining cellular homeostasis and stemness. The dysregulation of NAD+ levels with age has been associated with metabolic disorders and the loss of stemness. In this study, we aimed to investigate the effects of nicotinamide riboside (NR), a precursor of NAD+, on the stemness of human ASCs in cell culture. Our findings reveal that adipogenesis is accompanied by an increase in mitochondrial activity and the production of reactive oxygen species (ROS). However, treatment with NR leads to a reduction in mitochondrial activity and ROS production in ASCs. Furthermore, NR administration improves the stemness-related genes expression in ASCs and mitigates their propensity for adipocyte differentiation. These results suggest that NR treatment holds promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using animal models and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established drug for enhancing the stemness of aged stem cells.

Keywords:  adipose stem cells; adipose tissue; differentiation; nicotinamide riboside; proliferation; reactive oxygen species; stemness

DOI:  https://doi.org/10.3390/ph16081134
Autophagy. 2023 Aug 23.

Autophagy preserves hematopoietic stem cells by restraining MTORC1-mediated cellular anabolism.

Mariana Borsa, Sandrine Obba, Felix C Richter, Hanlin Zhang, Thomas Riffelmacher, Joana Carrelha, Ghada Alsaleh, Sten Eirik W Jacobsen, Anna Katharina Simon.

  Adult stem cells are long-lived and quiescent with unique metabolic requirements. Macroautophagy/autophagy is a fundamental survival mechanism that allows cells to adapt to metabolic changes by degrading and recycling intracellular components. Here we address why autophagy depletion leads to a drastic loss of the stem cell compartment. Using inducible deletion of autophagy specifically in adult hematopoietic stem cells (HSCs) and in mice chimeric for autophagy-deficient and normal HSCs, we demonstrate that the stem cell loss is cell-intrinsic. Mechanistically, autophagy-deficient HSCs showed higher expression of several amino acid transporters (AAT) when compared to autophagy-competent cells, resulting in increased amino acid (AA) uptake. This was followed by sustained MTOR (mechanistic target of rapamycin) activation, with enlarged cell size, glucose uptake and translation, which is detrimental to the quiescent HSCs. MTOR inhibition by rapamycin treatment in vivo was able to rescue autophagy-deficient HSC loss and bone marrow failure and resulted in better reconstitution after transplantation. Our results suggest that targeting MTOR may improve aged stem cell function, promote reprogramming and stem cell transplantation.

Keywords:  Autophagy; MTOR; amino acids; hematopoietic stem cells; rapamycin; translation

DOI:  https://doi.org/10.1080/15548627.2023.2247310
Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01043-4. [Epub ahead of print]42(9): 113032

Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.

Eloïse Marques, Maraiza Alves Teixeira, Clément Nguyen, Fabiola Terzi, Morgan Gallazzini.

  Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.

Keywords:  CP: Metabolism; Lipocalin-2; kidney; mTOR pathway; mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.celrep.2023.113032