bims-cesemi 2024-12-22 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–12–22
seventeen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Mitochondrial metabolism and epigenetic crosstalk drive the SASP.
Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.
Mapping mitochondrial aging.
Aged neurons don't register energy need.
Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
Biomarkers of cellular senescence and major health outcomes in older adults.
A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress.
Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.
Why eating less slows ageing: this molecule is key.
Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
NAD+ Boosting Strategies.
Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.
Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.

Res Sq. 2024 Dec 05. pii: rs.3.rs-5278203. [Epub ahead of print]

Mitochondrial metabolism and epigenetic crosstalk drive the SASP.

Joao Passos, Helene Martini, Jodie Birch, Francisco Marques, Stella Victorelli, Anthony Lagnado, Nicholas Pirius, Ana Franco, Gung Lee, Yeaeun Han, Jennifer Rowsey, Alexandre Gaspar-Maia, Aaron Havas, Rabi Murad, Xue Lei, Rebecca Porritt, Oliver Maddocks, Diana Jurk, Sundeep Khosla, Peter Adams.

Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

DOI: https://doi.org/10.21203/rs.3.rs-5278203/v1
Biogerontology. 2024 Dec 20. 26(1): 29

Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.

Ray Jiménez, Alejandra Zúñiga-Muñoz, Edith Álvarez-León, Wylly Ramsés García-Niño, Gabriela Navarrete-Anastasio, Elizabeth Soria-Castro, Israel Pérez-Torres, Elizabeth Lira-Silva, Natalia Pavón, Alfredo Cruz-Gregorio, Rebeca López-Marure, Cecilia Zazueta, Alejandro Silva-Palacios.

  Cardiomyocyte senescence plays a crucial role in the pathophysiology of age-related cardiovascular disease. Senescent cells with impaired contractility, mitochondrial dysfunction, and hypertrophic growth accumulate in the heart during aging, contributing to cardiac dysfunction and remodeling. Mitochondrial dynamics is altered in aging cells, leading to changes in their function and morphology. Such rearrangements can affect the spatially restricted region of the mitochondrial membrane that interacts with reticulum membrane fragments, termed mitochondria-endoplasmic reticulum (ER) contact sites (MERCs). Besides, oxidative stress associated with inefficient organelle turnover can drive cellular senescence. Therefore, in this study, we evaluated the possible association between the senolytic effect of the antioxidant quercetin (Q) and MERCs preservation in a D-galactose-induced cellular senescence model. We found that Q ameliorates the senescent phenotype of H9c2 cells in association with increased mitochondria-ER colocalization, reduced distance between both organelles, and lower ROS production. Moreover, regulation of fusion and fission processes was related with increased mitochondrial ATP production and enhanced transmembrane potential. Overall, our data provide evidence that the inhibitory effect of Q on cellular senescence is associated with preserved MERCs and improved mitochondrial function and morphology, which might contribute to the attenuation of cardiac dysfunction.

Keywords:  Cardiac senescence; Mitochondria-endoplasmic reticulum contact sites; Mitochondrial dynamic; Quercetin; Senolysis

DOI:  https://doi.org/10.1007/s10522-024-10174-y
Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

  Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.105191
Science. 2024 Dec 20. 386(6728): 1349-1350

Aged neurons don't register energy need.

Deniz Bingul, Scott F Owen.

Neuronal activity and mitochondrial gene expression become decoupled in aged mice.

DOI: https://doi.org/10.1126/science.adu4935
Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w
Cell Mol Biol Lett. 2024 Dec 18. 29(1): 153

Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.

Meng Zhang, Jin Wei, Chang He, Liutao Sui, Chucheng Jiao, Xiaoyan Zhu, Xudong Pan.

  Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.

Keywords:  Age-related diseases; Aging; Mitochondrial communication; Mitochondrial dysfunction; Signaling hubs

DOI:  https://doi.org/10.1186/s11658-024-00669-4
Nat Metab. 2024 Dec;6(12): 2215-2217

Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.

Fiona M Fitzpatrick, Nora Kory.

DOI: https://doi.org/10.1038/s42255-024-01160-2
Geroscience. 2024 Dec 18.

Biomarkers of cellular senescence and major health outcomes in older adults.

Steven R Cummings, Li-Yung Lui, Aversa Zaira, Theresa Mau, Roger A Fielding, Elizabeth J Atkinson, Sheena Patel, Nathan LeBrasseur.

  The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70-79 years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5 year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Keywords:  Biomarkers; Cell senescence; Geroscience; Senescence associated secretory phenotype

DOI:  https://doi.org/10.1007/s11357-024-01474-9
Cell Calcium. 2024 Dec 13. pii: S0143-4160(24)00144-1. [Epub ahead of print]125 102986

A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress.

Leandro C Clementino, Andrew P Thomas, Emily M Rocha, Sabine Hilfiker.

  Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca2+ channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.

Keywords:  Calcium signaling; Lysosome; Mitophagy; Reactive oxygen species; TFEB; TRPML1

DOI:  https://doi.org/10.1016/j.ceca.2024.102986
Cell Death Dis. 2024 Dec 18. 15(12): 902

Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.

Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida.

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.

DOI: https://doi.org/10.1038/s41419-024-07284-3
Nature. 2024 Dec 18.

Why eating less slows ageing: this molecule is key.

Heidi Ledford.



Keywords:  Ageing; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-04220-5
Annu Rev Physiol. 2024 Dec 10.

Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?

David J Bishop, Matthew J-C Lee, Martin Picard.

Mitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.

DOI: https://doi.org/10.1146/annurev-physiol-022724-104836
Int J Mol Sci. 2024 Nov 27. pii: 12740. [Epub ahead of print]25(23):

Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.

Alexander V Panov, Vladimir I Mayorov, Sergey I Dikalov.

  In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation. We conclude that ATP production during fatty acid β-oxidation has its upper limits and thus cannot support high energy demands alone. Meanwhile, β-oxidation creates conditions that significantly accelerate the cycle: glucose-aerobic glycolysis-lactate-gluconeogenesis-glucose. Therefore, glycolytic ATP production becomes an important energy source in high energy demand. In addition, lactate serves as a mitochondrial substrate after converting to pyruvate + H+ by the mitochondrial lactate dehydrogenase. All coupled metabolic pathways are irreversible, and the enzymes are organized into multienzyme structures.

Keywords:  aerobic glycolysis; beta-oxidation; fatty acids; gluconeogenesis; lactate; metabolism; mitochondria; respirasome

DOI:  https://doi.org/10.3390/ijms252312740
Subcell Biochem. 2024 ;107 63-90

NAD+ Boosting Strategies.

Jared Rice, Sofie Lautrup, Evandro F Fang.

  Nicotinamide adenine dinucleotide (oxidized form, NAD+) serves as a co-substrate and co-enzyme in cells to execute its key roles in cell signalling pathways and energetic metabolism, arbitrating cell survival and death. It was discovered in 1906 by Arthur Harden and William John Young in yeast extract which could accelerate alcohol fermentation. NAD acts as an electron acceptor and cofactor throughout the processes of glycolysis, Tricarboxylic Acid Cycle (TCA), β oxidation, and oxidative phosphorylation (OXPHOS). NAD has two forms: NAD+ and NADH. NAD+ is the oxidising coenzyme that is reduced when it picks up electrons. NAD+ levels steadily decline with age, resulting in an increase in vulnerability to chronic illness and perturbed cellular metabolism. Boosting NAD+ levels in various model organisms have resulted in improvements in healthspan and lifespan extension. These results have prompted a search for means by which NAD+ levels in the body can be augmented by both internal and external means. The aim of this chapter is to provide an overview of NAD+, appraise clinical evidence of its importance and success in potentially extending health- and lifespan, as well as to explore NAD+ boosting strategies.

Keywords:  Ageing; Caloric restriction; NAD+; Neurodegeneration; Nicotinamide mononucleotide; Nicotinamide riboside; Oxidative stress; Supplementation

DOI:  https://doi.org/10.1007/978-3-031-66768-8_4
Redox Biol. 2024 Dec 12. pii: S2213-2317(24)00445-2. [Epub ahead of print]79 103467

Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.

Chao Song, Wu Zheng, Guoming Liu, Yiyang Xu, Zhibo Deng, Yu Xiu, Rongsheng Zhang, Linhai Yang, Yifei Zhang, Guoyu Yu, Yibin Su, Jun Luo, Bingwei He, Jie Xu, Hanhao Dai.

  In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.

Keywords:  E-syt1; Mitochondria; Mitophagy; Myogenesis; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.redox.2024.103467
Cell. 2024 Nov 26. pii: S0092-8674(24)01311-4. [Epub ahead of print]

Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration.

Han Chen, Chao Liu, Shiyao Cui, Yingqian Xia, Ke Zhang, Hanxiao Cheng, Jingyu Peng, Xiaoling Yu, Luyang Li, Hualin Yu, Jufang Zhang, Ju-Sheng Zheng, Bing Zhang.

  Intermittent fasting has gained global popularity for its potential health benefits, although its impact on somatic stem cells and tissue biology remains elusive. Here, we report that commonly used intermittent fasting regimens inhibit hair follicle regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). This effect is independent of calorie reduction, circadian rhythm alterations, or the mTORC1 cellular nutrient-sensing mechanism. Instead, fasting activates crosstalk between adrenal glands and dermal adipocytes in the skin, triggering the rapid release of free fatty acids into the niche, which in turn disrupts the normal metabolism of HFSCs and elevates their cellular reactive oxygen species levels, causing oxidative damage and apoptosis. A randomized clinical trial (NCT05800730) indicates that intermittent fasting inhibits human hair growth. Our study uncovers an inhibitory effect of intermittent fasting on tissue regeneration and identifies interorgan communication that eliminates activated HFSCs and halts tissue regeneration during periods of unstable nutrient supply.

Keywords:  hair follicle regeneration; hair follicle stem cells; hair growth; intermittent fasting; somatic stem cells

DOI:  https://doi.org/10.1016/j.cell.2024.11.004
Front Mol Neurosci. 2024 ;17 1504802

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy.

Michael Aschner, Anatoly V Skalny, Rongzhu Lu, Airton C Martins, Yousef Tizabi, Sergey V Nekhoroshev, Abel Santamaria, Anton I Sinitskiy, Alexey A Tinkov.

  Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Keywords:  copper; cuproptosis; fission; mitochondrial fusion; mitophagy

DOI:  https://doi.org/10.3389/fnmol.2024.1504802