bims-cesemi 2026-07-26 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2026–07–26
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor

TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.
Senescent Cells in Wounds: Beneficial, Neutral, or Harmful?
Selective targeting of cancer and senescence via shared metabolic shifts extends lifespan of old mice.
When calcium crosstalk turns ferroptotic: the SERCA2-VDAC1 axis in AKI.
Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.
Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.

Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00781-3. [Epub ahead of print]45(7): 117703

TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.

Jiamin Huang, Yayu Wang, Yudong Xu, Yanan Wei, Xiang Yin, Junling Li, Yu Zeng, Meiting Chen, Canjun Li, Li Wang, Xiaomei Li, Lili Qu, Chunlei Cang.

  Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

Keywords:  CLN7; CP: molecular biology; ERK; HSP90; TTYH3; autophagy; chloride conductance; lysosome; lysosome fusion; mTOR; senescence

DOI:  https://doi.org/10.1016/j.celrep.2026.117703
J Invest Dermatol. 2026 Jul 23. pii: S0022-202X(26)02685-0. [Epub ahead of print]

Senescent Cells in Wounds: Beneficial, Neutral, or Harmful?

Grace T Yu, Robert S Kirsner, James L Kirkland, Saranya P Wyles.



Keywords:  aging; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinase inhibitor p21; regeneration; senolytic

DOI:  https://doi.org/10.1016/j.jid.2026.06.1295
Aging (Albany NY). 2026 Jul 17. 18(1): 868-892

Selective targeting of cancer and senescence via shared metabolic shifts extends lifespan of old mice.

Zachery R Robinson, Sabrina C Fong, Daniella Y Choi, Sophia Siopack, Alexander Bolanos-Campos, Negar Morshedian, Eva Utke, Mayuka Ninomiya Kanda, Cameron Kato, Michael J Conboy, Irina M Conboy.

  Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells. We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.

Keywords:  ATP; aging; cancer; metabolic shift; senescence

DOI:  https://doi.org/10.18632/aging.206399
Kidney Int. 2026 Aug;pii: S0085-2538(26)00415-1. [Epub ahead of print]110(2): 297-300

When calcium crosstalk turns ferroptotic: the SERCA2-VDAC1 axis in AKI.

Yu Ah Hong.

Organelle communication through endoplasmic reticulum-mitochondrial crosstalk is essential for maintaining cellular homeostasis and is tightly regulated by tethering proteins within mitochondria-associated endoplasmic reticulum membranes. In a recent study published in Kidney International, He et al. identified sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 as a key regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in proximal tubules and demonstrated that loss of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 drives voltage-dependent anion channel 1 oligomerization, mitochondrial DNA release, stimulator of interferon genes activation, and ferroptosis in acute kidney injury. This study establishes the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2-voltage-dependent anion channel 1 axis as a mechanistic link between mitochondrial calcium dysregulation and ferroptotic tubular injury.

DOI: https://doi.org/10.1016/j.kint.2026.05.005
EMBO J. 2026 Jul 22.

Tripartite ER-mitochondria-lipid droplets contact sites control adipocyte metabolic flexibility.

Marie Palard, Gilliane Chadeuf, Maxime Carpentier, Clotilde C N Renaud, Samuel Frey, Mikael Croyal, Rola Shaaban, Samy Hadjadj, Chloe Cloteau, Naima El Khallouki, Perrine Bomme, Soazig Le Lay, Manuel Majrouh, Perrine Paul-Gilloteaux, Alexandre Humbert, Christine Durand, Nicolas Bertocchini, Laurence Dubreil, Yoann Combot, Antria Antreou, Cedric Le May, Simon Ducheix, Bertrand Cariou, Francesca Giordano, Jennifer Rieusset, Abdou Rachid Thiam, Xavier Prieur.

Adipocyte dysfunction is a major driver of obesity-associated cardiometabolic disease, underscoring the need to understand how lipid storage and mobilization are regulated and disrupted. The ER-anchored protein Seipin governs lipid droplet (LD) biogenesis and ER-LD and ER-mitochondria (MAM) contacts, and its loss impairs calcium transfer and causes lipodystrophy. Here, we investigated whether Seipin coordinates MAM and ER-LD remodeling during adipocyte lipid handling. In subcutaneous adipose tissue from inducible Seipin-knockout mice, electron microscopy and proximity ligation assays revealed that feeding reduces MAMs while increasing ER-LD and mitochondria-LD contacts, a remodeling abolished by Seipin deficiency. Lipid loading elevated tripartite MAM-LD contacts in controls but not knockouts. Fluorescence recovery after photobleaching showed that impaired triglyceride transfer to LDs in Seipin-deficient cells was rescued by the MAM-LD-stabilizing peptide 'Linker-ER-Mi', in a calcium-dependent manner. During adipogenesis and lipid loading, MAM-LD contacts increased, whereas MAM-cytosolic mitochondria contacts declined; however, obesity blunted this remodeling. Furthermore, disrupting membrane contact sites impaired lipid flux, lipolysis, and insulin signaling. Taken together, these findings identify MAM-LD as regulators of adipocyte metabolic flexibility.

DOI: https://doi.org/10.1038/s44318-026-00876-z
Smart Med. 2026 Jun;5(3): e70043

Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.

Yixiang Zhang, Yawei Du, Shifeng Ling, Hanqi Wang, Jiahao He, Jiahong Li, Kaifeng Huo, Baikun Liu, Qingfeng Li, Jiao Wei, Wenguo Cui.

  Adipose-derived stem cells (ADSCs) are central regulators of adipose tissue homeostasis and regenerative capacity. Accumulating evidence indicates that aging and obesity profoundly impair ADSC function, through progressive mitochondrial dysfunction and disrupted mitochondrial-nuclear communication. Emerging studies reveal that defects in nuclear-mitochondrial crosstalk constitute a key driver of ADSC senescence and adipose tissue aging. In this review, we synthesize recent advances in understanding the mitochondrial mechanisms underlying ADSC aging, with particular emphasis on how mitochondrial dysfunction reshapes stem cell fate decisions, metabolic plasticity, and inflammatory signaling within aged adipose niches. We further highlight mitochondria targeting therapeutic strategies that hold promise for reversing ADSC senescence. Collectively, this framework positions mitochondrial regulation as a unifying axis for ADSC rejuvenation, offering new opportunities to restore adipose tissue homeostasis and mitigate age-related metabolic dysfunction.

Keywords:  adipose derived stem cell; aging; cellular communication; mitochondria; mtDNA

DOI:  https://doi.org/10.1002/smmd.70043
Nat Metab. 2026 Jul 23.

Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.

Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.

Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.

DOI: https://doi.org/10.1038/s42255-026-01578-w