bims-cesemi 2025-04-20 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–04–20
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Mechanism of MCUB-Dependent Inhibition of Mitochondrial Calcium Uptake.
Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.
Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.
Rationale and Design of STAMINA: Senolytics To Alleviate Mobility Issues and Neurological Impairments in Aging, A Geroscience Feasibility Study.
From geroscience to precision geromedicine: Understanding and managing aging.
Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
ALDH1A3 Regulates Cellular Senescence and Senescence-Associated Secretome in Prostate Cancer.
Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.

J Cell Physiol. 2025 Apr;240(4): e70033

Mechanism of MCUB-Dependent Inhibition of Mitochondrial Calcium Uptake.

Neeraj K Rai, David R Eberhardt, Anthony M Balynas, Melissa J S MacEwen, Ashley R Bratt, Yasemin Sancak, Dipayan Chaudhuri.

  Mitochondrial Ca2+ levels are regulated to balance stimulating respiration against the harm of Ca2+ overload. Contributing to this balance, the main channel transporting Ca2+ into the matrix, the mitochondrial Ca2+ uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca2+ transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca2+ uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca2+ uptake, suggesting the mechanism of inhibition may involve more global domain rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca2+ influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca2+ transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca2+ transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca2+ uptake.

Keywords:  EMRE; Förster resonance energy transfer; MICU1; calcium channels; ischemia‐reperfusion injury; mitochondrial calcium uniporter

DOI:  https://doi.org/10.1002/jcp.70033
Nat Commun. 2025 Apr 17. 16(1): 3401

Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering.

Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

DOI: https://doi.org/10.1038/s41467-025-58538-3
Cell Calcium. 2025 Apr 08. pii: S0143-4160(25)00026-0. [Epub ahead of print]127 103017

Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.

Kriti Ahuja, Rajender K Motiani.

  Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca2+), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca2+signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca2+uptake through silencing of Mitochondrial Ca2+Uniporter (MCU) leads to Ca2+oscillations in the cytosol. The rise in cytosolic Ca2+ results in activation of Ca2+ sensitive transcription factors such as NFATs and NF-κB. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca2+ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.

Keywords:  Calcium sensitive transcription factors; Mitochondrial calcium signaling; Nuclear transcription; Retrograde signaling

DOI:  https://doi.org/10.1016/j.ceca.2025.103017
Transl Med Aging. 2023 ;7 109-117

Rationale and Design of STAMINA: Senolytics To Alleviate Mobility Issues and Neurological Impairments in Aging, A Geroscience Feasibility Study.

Courtney L Millar, Ike Iloputaife, Kathryn Baldyga, Jasmin Kuo, Tamara Tchkonia, James L Kirkland, Thomas G Travison, Lewis A Lipsitz.

  The process of cellular senescence is hypothesized to play a critical role in the development of age-related mobility and cognitive impairments, both of which precede the development of Alzheimer's disease. Therefore, senolytic compounds that eliminate senescent cells represent an alternative strategy that may help improve mobility and cognition in older adults; however, clinical trials are lacking. The goal of this paper is to describe the rationale and study design of a 12-week single arm, open label, pre-post pilot study that administers intermittent doses of two senolytic compounds, Dasatinib and quercetin (DQ), in 12 older adults ≥ 65 years with slow gait speed (<1.0 m/sec) and mild cognitive impairment. Eligible participants are asked to take 1250 mg of and 100 mg of Dasatinib orally once a day for 2 days every 2 weeks, for 6 cycles over 12 consecutive weeks. Both physical and cognitive functional assessments are administered before treatment, as well as 6- and 12- weeks after treatment. Blood and urine samples are taken pre- and post-treatment to assess biomarkers of cellular senescence. The primary outcomes of this trial are feasibility and safety of the intervention, as well as preliminary efficacy on several clinical outcomes (e.g., cerebral blood flow velocity, gait speed, and biomarkers of cellular senescence). The study is approved by the Advarra IRB (#Pro00053594) and a Data Safety Monitoring Board. It is registered at Clinicaltrials.gov (Identifier:NCT05422885). The future results of this study may identify a novel approach for improving mobility and cognition in older adults, thereby preventing progression to Alzheimer's disease.

Keywords:  Aging; Cognitive Impairment; Flavonoids; Gait; Senolytics

DOI:  https://doi.org/10.1016/j.tma.2023.10.004
Cell. 2025 Apr 17. pii: S0092-8674(25)00284-3. [Epub ahead of print]188(8): 2043-2062

From geroscience to precision geromedicine: Understanding and managing aging.

Guido Kroemer, Andrea B Maier, Ana Maria Cuervo, Vadim N Gladyshev, Luigi Ferrucci, Vera Gorbunova, Brian K Kennedy, Thomas A Rando, Andrei Seluanov, Felipe Sierra, Eric Verdin, Carlos López-Otín.

  Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors. Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans. Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation. New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine. It is anticipated that, pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures.

Keywords:  aging; aging clocks; anti-aging drugs; atherosclerosis; cancer; cardiovascular diseases; diabetes; epigenetic clocks; genomics; neurodegeneration; oncogene; oncosuppression; primary prevention

DOI:  https://doi.org/10.1016/j.cell.2025.03.011
Sci Adv. 2025 Apr 18. 11(16): eads1842

Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.

Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.

Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.

DOI: https://doi.org/10.1126/sciadv.ads1842
Cancers (Basel). 2025 Mar 31. pii: 1184. [Epub ahead of print]17(7):

ALDH1A3 Regulates Cellular Senescence and Senescence-Associated Secretome in Prostate Cancer.

Sen Wang, Lin Wang, Yu Zhao.

  Background: Radiotherapy is a key treatment for cancer, effectively controlling local tumor growth through DNA damage that induces senescence or apoptosis in cancer cells. However, radiotherapy can trigger complex cellular reactions, such as cell senescence, which is characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors known as the senescent-associated secretory phenotype (SASP). Methods: This study investigates the regulatory role of ALDH1A3, a key enzyme implicated in cancer cell metabolism and radiotherapy resistance, in the induction of senescence and SASP. Using in vitro models, we demonstrate that ALDH1A3 knockdown accelerates cellular senescent-like phenotype while regulating the SASP through the cGAS-STING immune response pathway. Results: Our results indicate that while ALDH1A3 knockdown promotes senescence, it reduces the secretion of pro-inflammatory factors via inhibition of the cGAS-STING pathway, potentially mitigating SASP-related tumor progression. Conclusions: These findings provide insights into the molecular mechanisms underlying prostate cancer cell senescence and suggest that ALDH1A3 could be a potential therapeutic target to enhance the efficacy of radiotherapy while controlling the adverse effects of SASP.

Keywords:  ALDH1A3; SASP; cGAS–STING; cellular senescence; radiotherapy

DOI:  https://doi.org/10.3390/cancers17071184
Nat Commun. 2025 Apr 16. 16(1): 3306

Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.

Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.

The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.

DOI: https://doi.org/10.1038/s41467-025-57238-2
iScience. 2025 Apr 18. 28(4): 112283

Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.

Ying Pang, Qi Li, Zach Sergi, Guangyang Yu, Olga Kim, Peng Lu, Marina Chan, Xueyu Sang, Herui Wang, Alice Ranjan, Robert W Robey, Ferri Soheilian, Bao Tran, Felipe J Núñez, Meili Zhang, Hua Song, Wei Zhang, Dionne Davis, Mark R Gilbert, Michael M Gottesman, Zhenggang Liu, Craig J Thomas, Maria G Castro, Taranjit S Gujral, Jing Wu.

  Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that potentially render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).

Keywords:  Cancer; Therapeutics

DOI:  https://doi.org/10.1016/j.isci.2025.112283