bims-cesemi 2024-05-12 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–05–12
thirteen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Role of the gut-muscle axis in mitochondrial function of ageing muscle under different exercise modes.
The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.
Mitochondrial calcium regulation of cardiac metabolism in health and disease.
Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes.
Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.
Mitochondria regulate proliferation in adult cardiac myocytes.
Aging clocks based on accumulating stochastic variation.
Reprogrammed mitochondria: a central hub of cancer cell metabolism.
Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.
Mitochondrial transplantation: A promising therapy for mitochondrial disorders.
Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury.
Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
Reactive oxygen species promote endurance exercise-induced adaptations in skeletal muscles.

Ageing Res Rev. 2024 May 03. pii: S1568-1637(24)00134-X. [Epub ahead of print]98 102316

Role of the gut-muscle axis in mitochondrial function of ageing muscle under different exercise modes.

Xiaoting Xie, Cong Huang.

  The fundamental role of the gut microbiota through the gut-muscle axis in skeletal muscle ageing is increasingly recognised. Metabolites derived from the intestinal microbiota are essential in maintaining skeletal muscle function and metabolism. The energy produced by mitochondria and moderate levels of reactive oxygen species can contribute to this process. Metabolites can effectively target the mitochondria, slowing the progression of muscle ageing and potentially representing a marker of ageing-related skeletal muscle loss. Moreover, mitochondria can contribute to the immune response, gut microbiota biodiversity, and maintenance of the intestinal barrier function. However, the causal relationship between mitochondrial function and gut microbiota crosstalk remains poorly understood. In addition to elucidating the regulatory pathways of the gut-muscle axis during the ageing process, we focused on the potential role of the "exercise-gut-muscle axis", which represents a pathway under stimulation from different exercise modes to induce mitochondrial adaptations, skeletal muscle metabolism and maintain intestinal barrier function and biodiversity stability. Meanwhile, different exercise modes can induce mitochondrial adaptations and skeletal muscle metabolism and maintain intestinal barrier function and biodiversity. Resistance exercise may promote mitochondrial adaptation, increase the cross-sectional area of skeletal muscle and muscle hypertrophy, and promote muscle fibre and motor unit recruitment. Whereas endurance exercise promotes mitochondrial biogenesis, aerobic capacity, and energy utilisation, activating oxidative metabolism-related pathways to improve skeletal muscle metabolism and function. This review describes the effects of different exercise modes through the gut-muscle axis and how they act through mitochondria in ageing to define the current state of the field and issues requiring resolution.

Keywords:  Ageing; Exercise; Gut microbiota; Gut-muscle axis; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.arr.2024.102316
iScience. 2024 May 17. 27(5): 109699

The MCU and MCUb amino-terminal domains tightly interact: mechanisms for low conductance assembly of the mitochondrial calcium uniporter complex.

Megan Noble, Danielle M Colussi, Murray Junop, Peter B Stathopulos.

  The mitochondrial calcium (Ca2+) uniporter (MCU) complex is regulated via integration of the MCU dominant negative beta subunit (MCUb), a low conductance paralog of the main MCU pore forming protein. The MCU amino (N)-terminal domain (NTD) also modulates channel function through cation binding to the MCU regulating acidic patch (MRAP). MCU and MCUb have high sequence similarities, yet the structural and functional roles of MCUb-NTD remain unknown. Here, we report that MCUb-NTD exhibits α-helix/β-sheet structure with a high thermal stability, dependent on protein concentration. Remarkably, MCU- and MCUb-NTDs heteromerically interact with ∼nM affinity, increasing secondary structure and stability and structurally perturbing MRAP. Further, we demonstrate MCU and MCUb co-localization is suppressed upon NTD deletion concomitant with increased mitochondrial Ca2+ uptake. Collectively, our data show that MCU:MCUb NTD tight interactions are promoted by enhanced regular structure and stability, augmenting MCU:MCUb co-localization, lowering mitochondrial Ca2+ uptake and implicating an MRAP-sensing mechanism.

Keywords:  Cell biology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2024.109699
Physiology (Bethesda). 2024 May 07.

Mitochondrial calcium regulation of cardiac metabolism in health and disease.

Enrique Balderas, Sandra Hj Lee, Neeraj K Rai, David M Mollinedo, Hannah E Duron, Dipayan Chaudhuri.

  Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, while Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms, but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+-Ca2+ exchanger and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Keywords:  MCU; heart failure; ischemia reperfusion injury; mitochondrial calcium transport; mitochondrial cardiomyopathy

DOI:  https://doi.org/10.1152/physiol.00014.2024
Aging Cell. 2024 May 06. e14113

Clinical validation of C12FDG as a marker associated with senescence and osteoarthritic phenotypes.

William S Hambright, Victoria R Duke, Adam D Goff, Alex W Goff, Lucas T Minas, Heidi Kloser, Xueqin Gao, Charles Huard, Ping Guo, Aiping Lu, John Mitchell, Michael Mullen, Charles Su, Tamara Tchkonia, Jair M Espindola Netto, Paul D Robbins, Laura J Niedernhofer, James L Kirkland, Chelsea S Bahney, Marc Philippon, Johnny Huard.

  Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

Keywords:  aging; cell senescence; osteoarthritis; senolytics

DOI:  https://doi.org/10.1111/acel.14113
Aging (Albany NY). 2024 May 09. 16

Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.

Somaiah Chinnapaka, Hamid Malekzadeh, Zayaan Tirmizi, Asim Ejaz.

  Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.

Keywords:  adipose stem cells; adipose tissue; autophagy; caloric restriction; differentiation; reactive oxygen species; senescence; stemness

DOI:  https://doi.org/10.18632/aging.205812
J Clin Invest. 2024 May 09. pii: e165482. [Epub ahead of print]

Mitochondria regulate proliferation in adult cardiac myocytes.

Gregory B Waypa, Kimberly A Smith, Paul T Mungai, Vincent J Dudley, Kathryn A Helmin, Benjamin D Singer, Clara Bien Peek, Joseph Bass, Lauren Beussink-Nelson, Sanjiv J Shah, Gaston Ofman, J Andrew Wasserstrom, William A Muller, Alexander V Misharin, G R Scott Budinger, Hiam Abdala-Valencia, Navdeep S Chandel, Danijela Dokic, Elizabeth T Bartom, Shuang Zhang, Yuki Tatekoshi, Amir Mahmoodzadeh, Hossein Ardehali, Edward B Thorp, Paul T Schumacker.

  Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Keywords:  Bioenergetics; Cardiology; Cardiovascular disease; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI165482
Nat Aging. 2024 May 09.

Aging clocks based on accumulating stochastic variation.

David H Meyer, Björn Schumacher.

Aging clocks have provided one of the most important recent breakthroughs in the biology of aging, and may provide indicators for the effectiveness of interventions in the aging process and preventive treatments for age-related diseases. The reproducibility of accurate aging clocks has reinvigorated the debate on whether a programmed process underlies aging. Here we show that accumulating stochastic variation in purely simulated data is sufficient to build aging clocks, and that first-generation and second-generation aging clocks are compatible with the accumulation of stochastic variation in DNA methylation or transcriptomic data. We find that accumulating stochastic variation is sufficient to predict chronological and biological age, indicated by significant prediction differences in smoking, calorie restriction, heterochronic parabiosis and partial reprogramming. Although our simulations may not explicitly rule out a programmed aging process, our results suggest that stochastically accumulating changes in any set of data that have a ground state at age zero are sufficient for generating aging clocks.

DOI: https://doi.org/10.1038/s43587-024-00619-x
Biochem Soc Trans. 2024 May 08. pii: BST20231090. [Epub ahead of print]

Reprogrammed mitochondria: a central hub of cancer cell metabolism.

Fabio Ciccarone, Maria Rosa Ciriolo.

  Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.

Keywords:  TCA cycle; metabolic disorders; mitochondrial dysfunction

DOI:  https://doi.org/10.1042/BST20231090
Med Res Rev. 2024 May 06.

Targeting lysosomal quality control as a therapeutic strategy against aging and diseases.

Yuchen He, Yishu Fan, Xenab Ahmadpoor, Yumin Wang, Zhong Alan Li, Weihong Zhu, Hang Lin.

  Previously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome-dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.

Keywords:  aging; autoimmune diseases; cancer; degenerative diseases; lysosomal quality control

DOI:  https://doi.org/10.1002/med.22047
Int J Pharm. 2024 May 02. pii: S0378-5173(24)00428-9. [Epub ahead of print] 124194

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

Qiangqiang Jiao, Li Xiang, Yuping Chen.

  As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trial for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Keywords:  Artificial mitochondria; Clinical trials; Mitochondrial medicine; Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.ijpharm.2024.124194
Nat Aging. 2024 May 09.

Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury.

Jamil Nehme, Lina Mesilmany, Marta Varela-Eirin, Simone Brandenburg, Abdullah Altulea, Yao Lin, Mariana Gaya da Costa, Marc Seelen, Jan-Luuk Hillebrands, Harry van Goor, Raya Saab, Haidar Akl, Natacha Prevarskaya, Valerio Farfariello, Marco Demaria.

Excessive amounts of reactive oxygen species (ROS) lead to macromolecular damage and high levels of cell death with consequent pathological sequelae. We hypothesized that switching cell death to a tissue regenerative state could potentially improve the short-term and long-term detrimental effects of ROS-associated acute tissue injury, although the mechanisms regulating oxidative stress-induced cell fate decisions and their manipulation for improving repair are poorly understood. Here, we show that cells exposed to high oxidative stress enter a poly (ADP-ribose) polymerase 1 (PARP1)-mediated regulated cell death, and that blocking PARP1 activation promotes conversion of cell death into senescence (CODIS). We demonstrate that this conversion depends on reducing mitochondrial Ca2+ overload as a consequence of retaining the hexokinase II on mitochondria. In a mouse model of kidney ischemia-reperfusion damage, PARP inhibition reduces necrosis and increases transient senescence at the injury site, alongside improved recovery from damage. Together, these data provide evidence that converting cell death into transient senescence can therapeutically benefit tissue regeneration.

DOI: https://doi.org/10.1038/s43587-024-00627-x
Nat Commun. 2024 May 10. 15(1): 3982

Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.

Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.

The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.

DOI: https://doi.org/10.1038/s41467-024-48272-7
J Sport Health Sci. 2024 May 06. pii: S2095-2546(24)00062-0. [Epub ahead of print]

Reactive oxygen species promote endurance exercise-induced adaptations in skeletal muscles.

Scott K Powers, Zsolt Radak, Li Li Ji, Malcolm Jackson.

  The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field.

Keywords:  Antioxidants; Mitochondrial biogenesis; Radicals; Redox signaling

DOI:  https://doi.org/10.1016/j.jshs.2024.05.001