bims-cesemi 2024-06-02 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024‒06‒02
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor

Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.
A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.
Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.
Mitochondrial quality control in human health and disease.
mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming.
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.
Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.
The mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing) promotes glioblastoma tumorigenesis by modulating mitochondrial functions.
Bufotalin enhances apoptosis and TMZ chemosensitivity of glioblastoma cells by promoting mitochondrial dysfunction via AKT signaling pathway.
Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

Semin Cancer Biol. 2024 May 27. pii: S1044-579X(24)00036-1. [Epub ahead of print]

Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.

Birong Jiang, Wei Zhang, Xuguang Zhang, Yu Sun.

  Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.

Keywords:  senescence-associated secretory phenotype; senescent cell; senolytics; senotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2024.05.002
Redox Biol. 2024 May 22. pii: S2213-2317(24)00182-4. [Epub ahead of print]73 103204

A non-canonical role of ELN protects from cellular senescence by limiting iron-dependent regulation of gene expression.

Joanna Czarnecka-Herok, Kexin Zhu, Jean-Michel Flaman, Delphine Goehrig, Mathieu Vernier, Gabriela Makulyte, Aline Lamboux, Helena Dragic, Muriel Rhinn, Jean-Jacques Médard, Gilles Faury, Philippe Bertolino, Vincent Balter, Romain Debret, Serge Adnot, Nadine Martin, David Bernard.

  The ELN gene encodes tropoelastin which is used to generate elastic fibers that insure proper tissue elasticity. Decreased amounts of elastic fibers and/or accumulation of bioactive products of their cleavage, named elastokines, are thought to contribute to aging. Cellular senescence, characterized by a stable proliferation arrest and by the senescence-associated secretory phenotype (SASP), increases with aging, fostering the onset and progression of age-related diseases and overall aging, and has so far never been linked with elastin. Here, we identified that decrease in ELN either by siRNA in normal human fibroblasts or by knockout in mouse embryonic fibroblasts results in premature senescence. Surprisingly this effect is independent of elastic fiber degradation or elastokines production, but it relies on the rapid increase in HMOX1 after ELN downregulation. Moreover, the induction of HMOX1 depends on p53 and NRF2 transcription factors, and leads to an increase in iron, further mediating ELN downregulation-induced senescence. Screening of iron-dependent DNA and histones demethylases revealed a role for histone PHF8 demethylase in mediating ELN downregulation-induced senescence. Collectively, these results unveil a role for ELN in protecting cells from cellular senescence through a non-canonical mechanism involving a ROS/HMOX1/iron accumulation/PHF8 histone demethylase pathway reprogramming in gene expression towards a senescence program.

Keywords:  Cellular senescence; ELN; HMOX1; Iron; PHF8; ROS

DOI:  https://doi.org/10.1016/j.redox.2024.103204
Front Aging Neurosci. 2024 ;16 1384554

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.

Asha Rani, Linda Bean, Vivekananda Budamagunta, Ashok Kumar, Thomas C Foster.

  There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

Keywords:  aging; cognitive testing; hippocampus; senolytic; spatial memory

DOI:  https://doi.org/10.3389/fnagi.2024.1384554
Mil Med Res. 2024 May 29. 11(1): 32

Mitochondrial quality control in human health and disease.

Bo-Hao Liu, Chen-Zhen Xu, Yi Liu, Zi-Long Lu, Ting-Lv Fu, Guo-Rui Li, Yu Deng, Guo-Qing Luo, Song Ding, Ning Li, Qing Geng.

  Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.

Keywords:  Cancer; Cardiovascular disease; Digestive system disease; Kidney disease; Metabolic disease; Metabolism; Mitochondrial quality control; Nervous disease; Programmed cell death; Pulmonary disease

DOI:  https://doi.org/10.1186/s40779-024-00536-5
Elife. 2024 May 29. pii: RP92511. [Epub ahead of print]12

mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming.

Helmut Bischof, Selina Maier, Piotr Koprowski, Bogusz Kulawiak, Sandra Burgstaller, Joanna Jasińska, Kristian Serafimov, Monika Zochowska, Dominic Gross, Werner Schroth, Lucas Matt, David Arturo Juarez Lopez, Ying Zhang, Irina Bonzheim, Florian A Büttner, Falko Fend, Matthias Schwab, Andreas L Birkenfeld, Roland Malli, Michael Lämmerhofer, Piotr Bednarczyk, Adam Szewczyk, Robert Lukowski.

  Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the 'Warburg effect', thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.

Keywords:  K+ channels; Kcnma1; Slo1; Warburg effect; biosensors; breast cancer; cancer biology; cell biology; human; metabolic reprogramming; mitoBKCa; mouse

DOI:  https://doi.org/10.7554/eLife.92511
Nat Aging. 2024 May 30.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.

Goro Katsuumi, Ippei Shimizu, Masayoshi Suda, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Chieh-Lun Hsiao, Liang Jiaqi, Shinya Fujiki, Manabu Abe, Masataka Sugimoto, Tomoyoshi Soga, Tohru Minamino.

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

DOI: https://doi.org/10.1038/s43587-024-00642-y
Exp Gerontol. 2024 May 25. pii: S0531-5565(24)00107-4. [Epub ahead of print]193 112465

Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.

Claudia D C Navarro, Annelise Francisco, Ericka F D Costa, Ana P Dalla Costa, Marina R Sartori, Paulo F V Bizerra, Andréia R Salgado, Tiago R Figueira, Anibal E Vercesi, Roger F Castilho.

  Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt-/-) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt-/- mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt-/- mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt-/- mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.

Keywords:  Age-related muscle dysfunction; Locomotor impairment; Mitochondrial bioenergetics; NNT deficiency; Nicotinamide nucleotide transhydrogenase; Oxidative stress

DOI:  https://doi.org/10.1016/j.exger.2024.112465
bioRxiv. 2024 May 18. pii: 2024.05.15.594447. [Epub ahead of print]

The mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing) promotes glioblastoma tumorigenesis by modulating mitochondrial functions.

Ting Cai, Bei Zhang, Esha Reddy, Yuanna Wu, Yinglu Tang, Isha Mondal, Jerry Wang, Winson S Ho, Rongze Olivia Lu, Zhihao Wu.

The rapid and sustained proliferation in cancer cells requires accelerated protein synthesis. Accelerated protein synthesis and disordered cell metabolism in cancer cells greatly increase the risk of translation errors. ribosome-associated quality control (RQC) is a recently discovered mechanism for resolving ribosome collisions caused by frequent translation stalls. The role of the RQC pathway in cancer initiation and progression remains controversial and confusing. In this study, we investigated the pathogenic role of mitochondrial stress-induced protein carboxyl-terminal terminal alanine and threonine tailing (msiCAT-tailing) in glioblastoma (GBM), which is a specific RQC response to translational arrest on the outer mitochondrial membrane. We found that msiCAT-tailed mitochondrial proteins frequently exist in glioblastoma stem cells (GSCs). Ectopically expressed msiCAT-tailed mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein increases the mitochondrial membrane potential and blocks mitochondrial permeability transition pore (MPTP) formation/opening. These changes in mitochondrial properties confer resistance to staurosporine (STS)-induced apoptosis in GBM cells. Therefore, msiCAT-tailing can promote cell survival and migration, while genetic and pharmacological inhibition of msiCAT-tailing can prevent the overgrowth of GBM cells.Highlights: The RQC pathway is disturbed in glioblastoma (GBM) cellsmsiCAT-tailing on ATP5α elevates mitochondrial membrane potential and inhibits MPTP openingmsiCAT-tailing on ATP5α inhibits drug-induced apoptosis in GBM cellsInhibition of msiCAT-tailing impedes overall growth of GBM cells.

DOI: https://doi.org/10.1101/2024.05.15.594447
Aging (Albany NY). 2024 May 28. 16

Bufotalin enhances apoptosis and TMZ chemosensitivity of glioblastoma cells by promoting mitochondrial dysfunction via AKT signaling pathway.

Zhansheng Zhu, Shanwen Liang, Yu Hong, Yangzhi Qi, Qian Sun, Xinyi Zhu, Yuxin Wei, Yang Xu, Qianxue Chen.

  Glioblastoma multiforme (GBM) is the most prevalent and lethal primary intracranial neoplasm in the adult population, with treatments of limited efficacy. Recently, bufotalin has been shown to have anti-cancer activity in a variety of cancers. This investigation aims to investigate the effect of bufotalin on GBM and elucidate its potential underlying mechanism. Our results show that bufotalin not only inhibits the proliferation and epithelial-mesenchymal transition (EMT) but also triggers apoptosis in GBM cells. The result of RNA-seq indicated that bufotalin could induce mitochondrial dysfunction. Moreover, our observations indicate that bufotalin induces an excessive accumulation of intracellular reactive oxygen species (ROS) in GBM cells, leading to mitochondrial dysfunction and the dephosphorylation of AKT. Moreover, bufotalin improved TMZ sensitivity of GBM cells in vitro and in vivo. In conclusion, bufotalin enhances apoptosis and TMZ chemosensitivity of glioblastoma cells by promoting mitochondrial dysfunction via AKT signaling pathway.

Keywords:  AKT; ROS; TMZ sensitivity; apoptosis; bufotalin; mitochondrial dysfunction

DOI:  https://doi.org/10.18632/aging.205883
Geroscience. 2024 May 29.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

Amal A Wanigatunga, Fangyu Liu, Ryan J Dougherty, Karen Bandeen Roche, Jacek K Urbanek, Marta Zampino, Eleanor M Simonsick, Qu Tian, Jennifer A Schrack, Luigi Ferrucci.

  This study examined the association between in vivo skeletal mitochondrial function and digital free-living physical activity patterns-a measure that summarizes biological, phenotypic, functional, and environmental effects on mobility. Among 459 participants (mean age 68 years; 55% women) in the Baltimore Longitudinal Study of Aging, mitochondrial function was quantified as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected using a 7-day, 24-h wrist-worn protocol and summarized into activity amount, intensity, endurance, and accumulation patterning metrics. Linear regression, two-part linear and logistic (bout analyses), and linear mixed effects models (time-of-day analyses) were used to estimate associations between τPCr and each physical activity metric. Interactions by age, sex, and gait speed were tested. After covariate adjustment, higher τPCr (or poorer mitochondrial function) was associated with lower activity counts/day (β = - 6593.7, SE = 2406.0; p = 0.006) and activity intensity (- 81.5 counts, SE = 12.9; p < 0.001). For activity intensity, the magnitude of association was greater for men and those with slower gait speed (interaction p < 0.02 for both). Conversely, τPCr was not associated with daily active minutes/day (p = 0.15), activity fragmentation (p = 0.13), or endurance at any bout length (p > 0.05 for all). Time-of-day analyses show participants with high τPCr were less active from 6:00 a.m. to 12:00 a.m. than those with low τPCr. Results indicate that poorer skeletal mitochondrial function is primarily associated with lower engagement in high intensity activities. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behavior.

Keywords:  Aging; Digital biomarker; Movement; Muscle oxidative capacity; Technology; Wearables

DOI:  https://doi.org/10.1007/s11357-024-01212-1