Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells

Choudhury, Debanik; Na, Rong; Ikhapoh, Izuagie; Rajabian, Nika; Tseropoulos, Georgios; Wu, Yulun; Mehrotra, Pihu; Thiyagarajan, Ramkumar; Shahini, Aref; Seldeen, Kenneth L.; Troen, Bruce R.; Lei, Pedro; Andreadis, Stelios T.

doi:10.1016/j.celrep.2022.111744

Cited by 15 publications

(11 citation statements)

References 63 publications

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“…205 In HGPS, increased glutamine catabolism by GLS1 and decreased activity of the urea transporter SLC14A1 lead to mitochondrial functional abnormalities. 207 In mice expressing LMNA R133L , mitochondrial dysfunction is associated with decreased activity of the transcriptional repressor PGC-1α. 208 In such cells, decreased PGC-1α function is associated with sequestration of MYBBP1A by LMNA R133L .…”

Section: And Mitochondrial Proteostasis Network In Laminopathiesmentioning

confidence: 99%

“…211 In progeroid laminopathies, the main mitochondrial manifestations are loss of mitochondrial membrane potential (due to decreased COX2), altered dynamics of mitochondrial fusion and fission, mitochondrial DNA damage, fragmentation, and altered number of mitochondria, etc. Usually, such mitochondrial alterations are coupled with modulated JNK signaling in HGPS 207 and βadrenergic signaling in cardiac laminopathy, 212 resulting in visible cellular phenotypes such as lipid droplet accumulation, insulin resistance, high anabolic process, and low ATP level in laminopathic cells. Mitochondrial alterations eventually lead to excessive DNA damage, resulting in death of laminopathic cells by senescence.…”

Section: And Mitochondrial Proteostasis Network In Laminopathiesmentioning

confidence: 99%

“…Interestingly, the NAMPT‐NAD + pathway is downregulated due to decreased expression or chromatin recruitment of the transcriptional repressor PGC‐1α 205 . In HGPS, increased glutamine catabolism by GLS1 and decreased activity of the urea transporter SLC14A1 lead to mitochondrial functional abnormalities 207 …”

Section: Crosstalk Of Nuclear and Mitochondrial Proteostasis Network ...mentioning

confidence: 99%

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Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Pande

Ghosh

2023

The FASEB Journal

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Laminopathies are a group of rare genetic disorders with heterogeneous clinical phenotypes such as premature aging, cardiomyopathy, lipodystrophy, muscular dystrophy, microcephaly, epilepsy, and so on. The cellular phenomena associated with laminopathy invariably show disruption of nucleoskeleton of lamina due to deregulated expression, localization, function, and interaction of mutant lamin proteins. Impaired spatial and temporal tethering of lamin proteins to the lamina or nucleoplasmic aggregation of lamins are the primary molecular events that can trigger nuclear proteotoxicity by modulating differential protein–protein interactions, sequestering quality control proteins, and initiating a cascade of abnormal post‐translational modifications. Clearly, laminopathic cells exhibit moderate to high nuclear proteotoxicity, raising the question of whether an imbalance in nuclear proteostasis is involved in laminopathic diseases, particularly in diseases of early aging such as HGPS and laminopathy‐associated premature aging. Here, we review nuclear proteostasis and its deregulation in the context of lamin proteins and laminopathies.

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Section: And Mitochondrial Proteostasis Network In Laminopathiesmentioning

confidence: 99%

Section: And Mitochondrial Proteostasis Network In Laminopathiesmentioning

confidence: 99%

Section: Crosstalk Of Nuclear and Mitochondrial Proteostasis Network ...mentioning

confidence: 99%

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Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Pande

Ghosh

2023

The FASEB Journal

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“…Because senescent cells rely mainly on the glutamine catabolism for survival and the biosynthesis of SASP 24 , targeting the key enzyme GLS1 glutaminase with small inhibitory molecules (i.e. CB‐839, SP600125) could also restore age‐associated phenotypes, as demonstrated by Choudhury et al in a progeroid mouse model 25 . Another way to interfere with the SASP biosynthesis emerged from observations in patients infected with HIV under long active antiretroviral therapy, including certain protease inhibitors like atazanavir; such molecules (which target the ZMPSTE24 mammalian protease) cause accelerated premature senescence in these patients but treatment cessation seems to revert the senescent features and SASP production, as demonstrated in animal models 26 …”

Section: Figurementioning

confidence: 99%

“…CB-839, SP600125) could also restore age-associated phenotypes, as demonstrated by Choudhury et al in a progeroid mouse model. 25 Another way to interfere with the SASP biosynthesis emerged from observations in patients infected with HIV under long active antiretroviral therapy, including certain protease inhibitors like atazanavir; such molecules (which target the ZMPSTE24 mammalian protease) cause accelerated premature senescence in these patients but treatment cessation seems to revert the senescent features and SASP production, as demonstrated in animal models. 26 Nevertheless, findings from evidence-based medicine have changed some paradigms around the beneficial effect of SASP inhibition.…”

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confidence: 99%

Challenges in anti‐aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan

Popescu,

Deelen,

Illario

et al. 2023

J Cellular Molecular Medi

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We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co‐morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle‐independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno‐antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.

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Mitochondria, Autophagy and Inflammation: Interconnected in Aging

Silva

2024

Cell Biochem Biophys

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Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells

Cited by 15 publications

References 63 publications

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Nuclear proteostasis imbalance in laminopathy‐associated premature aging diseases

Challenges in anti‐aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan

Mitochondria, Autophagy and Inflammation: Interconnected in Aging

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