BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians

Borrás, Consuelo; Mas-Bargues, Cristina; Román-Domínguez, Aurora; Sanz-Ros, Jorge; Gimeno-Mallench, Lucía; Inglés, Marta; Gambini, Juan; Viña, José

doi:10.3390/ijms21020418

Cited by 33 publications

(28 citation statements)

References 93 publications

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“…Consistent with this, Bcl-xL seems to play a key role in the regulation of senescence, either directly or indirectly, through the modulation of intrinsic apoptosis, mitochondrial bioenergetics, oxidative stress and autophagy [ 101 ]. Since Bcl-xL could be a modulator of the harmful consequences of senescent cells accumulation, it would be of utmost interest to assess whether Bcl-xL might also modulate SASP factors or senescence-derived extracellular vesicles cargo.…”

Section: Senescence Role In Exceptional Agingmentioning

confidence: 83%

“…Despite its well-documented anti-apoptotic role, Bcl-xL is also related to mitochondrial bioenergetics by modulating mitochondrial fusion and fission, increasing total mitochondrial biomass and enhancing the efficiency of the ATP synthesis by decreasing the proton leak within the F1F0 ATPase [ 101 , 102 ]. As cellular senescence can be both beneficial and detrimental for the organism, accordingly, Bcl-xL might play a dual role on senescence.…”

Section: Senescence Role In Exceptional Agingmentioning

confidence: 99%

“…Centenarians overexpress Bcl-xL [ 99 ], which plays a role in the regulation of senescence, either directly or indirectly, through the modulation of intrinsic apoptosis, mitochondrial bioenergetics, oxidative stress and autophagy [ 101 ]. In this scenario, centenarians have a fine-tuned control of apoptosis which enables them to avoid an excessive burden of senescent cells, together with a fully functional immune system that removes senescent cells on time.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Bcl-xL as a Modulator of Senescence and Aging

Mas-Bargues

Borrás

Viña

2021

IJMS

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Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.

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Section: Senescence Role In Exceptional Agingmentioning

confidence: 83%

Section: Senescence Role In Exceptional Agingmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Bcl-xL as a Modulator of Senescence and Aging

Mas-Bargues

Borrás

Viña

2021

IJMS

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“…To conclude, we have identified a novel role for the mitochondrial Ser protease HtrA2, previously implicated in apoptosis, in regulating some of the cytoskeletal changes occurring during radiation-induced senescence. HtrA2 thus joins the short list of proteins, including p53 and BclXL (BCL2L1), which modulate apoptotic cell death and cellular senescence (Borras et al, 2020; Vicencio et al, 2008). BCL2L1 also emerged in our screen as a gene whose KD enhanced the radiation-induced decrease in cell viability.…”

Section: Discussionmentioning

confidence: 99%

The Serine Protease HtrA2 mediates radiation-induced senescence in cancer cells

Hammer

Levin-Salomon

Yaeli-Slonim

et al. 2021

Preprint

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Radiation therapy can induce cellular senescence in cancer cells leading to short-term tumor growth arrest, yet increased long-term recurrence. To better understand the molecular mechanisms involved, we developed a model of radiation-induced senescence in cultured cancer cells, which exhibited a typical senescent phenotype, including upregulation of p53 and its target p21, followed by sustained reduction in cellular proliferation, changes in cell size and cytoskeleton organization, and senescence-associated beta-galactosidase activity. A functional siRNA screen using a cell death-related library identified the mitochondrial Ser protease HtrA2 as necessary for senescence development. Mass spectrometry-based proteomic profiling of the senescent cells indicated downregulation of proteins involved in cell cycle progression and DNA repair, and upregulation of proteins associated with malignancy, while irradiation with HtrA2 inhibition upregulated cell proliferation components. In search of direct HtrA2 substrates following radiation, we determined that HtrA2 cleaves the intermediate filament protein vimentin, affecting its cytoplasmic organization. Ectopic expression of active cytosolic HtrA2 resulted in similar changes to vimentin filament assembly. Thus HtrA2, contributes to several hallmarks of senescence and is involved in the cytoskeletal reorganization that accompanies radiation-induced senescence.

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“…Bcl-xL is encoded by the BCL2L1 gene, which is located on human chromosome 20 at band q11.21 and gives two isoforms of mature RNA through alternative splicing: the short form Bcl-xS, containing three exons, and the large form Bcl-xL, containing 4 exons [ 47 ]. At protein level, three different isoforms can be found: the longer form, containing 233 amino acid residues in length, acts as an apoptotic inhibitor; the shorter form, of 170 amino acid, acts as an activator of apoptosis; and a third form, called Bcl-xβ, containing 227 amino acids, differs from the longer and shorter forms in the last 45 amino acids, but does not display any specific functions [ 48 ] ( Figure 2 ) .…”

Section: Bcl-2 Familymentioning

confidence: 99%

Bcl-xL: A Focus on Melanoma Pathobiology

Luciano

Pérez-Oliva

Mulero

et al. 2021

IJMS

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Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors.

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BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians

Cited by 33 publications

References 93 publications

Bcl-xL as a Modulator of Senescence and Aging

Bcl-xL as a Modulator of Senescence and Aging

The Serine Protease HtrA2 mediates radiation-induced senescence in cancer cells

Bcl-xL: A Focus on Melanoma Pathobiology

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