bims-mihora 2026-05-03 papers

Issue of 2026–05–03
seven papers selected by
Lisa Patel, Istesso

Ageing Res Rev. 2026 Apr 25. pii: S1568-1637(26)00142-X. [Epub ahead of print] 103150

Mitochondrial-nuclear crosstalk: A central axis in Alzheimer's disease.

Kunal Samantaray, Anupriya Sinha, Dhanendra Tomar, Pooja Jadiya.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and survival pathways, making it a critical determinant of brain aging and AD vulnerability. Despite its importance, the mechanisms coordinating this bidirectional dialogue and how their breakdown drives neurodegeneration remain poorly understood. This review highlights the major molecular pathways governing mito-nuclear signaling under physiological conditions, including anterograde pathways (PGC-1α/NRF1/2/TFAM) and retrograde stress responses (ROS, calcium, mitokines, and the mitochondrial unfolded protein response). In AD, these pathways are disrupted, leading to mitochondrial dysfunction, impaired proteostasis, metabolic reprogramming, and inflammation. Emerging evidence suggests that mito‑nuclear signaling deficits arise early often preceding classical Aβ and tau pathology positioning them as potential upstream drivers of disease. We further discuss therapeutic strategies aimed at restoring mito‑nuclear communication, including NAD⁺ supplementation, mitophagy enhancers, mitochondria‑targeted antioxidants, and gene‑based approaches, emphasizing the importance of combinatorial and cell‑type‑specific interventions. Finally, we highlight how single‑cell and spatial transcriptomic technologies are enabling high‑resolution mapping of mito‑nuclear dynamics in aging and AD. Together, these insights underscore mito‑nuclear signaling as a promising but underexplored therapeutic target for modifying AD progression.

Keywords: Alzheimer’s disease; aging; bioenergetics; mito-nuclear crosstalk; mitochondrial dysfunction; neurodegeneration

DOI: https://doi.org/10.1016/j.arr.2026.103150

Sci Adv. 2026 May;12(18): eaea6630

The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells.

Seyoun Oh, Jeeyoon Chang, Hodam Jo, Jungwon Yoon, Sung Key Jang, Yoon Ki Kim, Jiwon Jang.

The integrated stress response (ISR) suppresses global translation while allowing selective synthesis of key regulatory proteins. However, how translation persists during ISR remains unclear. In eukaryotes, the 5'-cap of mRNAs is bound by either the cap-binding complex (CBC) or eIF4E. We show that under stress, CBC-bound mRNAs recruit eIF2A, an alternative initiation factor, to sustain translation when eIF4E-dependent translation is inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue proliferating due to a compensatory increase in eIF2A. This increase ensures CBC-dependent translation (CT) of essential cell cycle regulators. Notably, yes-associated protein (YAP), a key proliferation factor, is a major CT target driving stress-resistant stem cell proliferation. Our findings reveal CT as a critical pathway that preserves protein synthesis and proliferation under stress.

DOI: https://doi.org/10.1126/sciadv.aea6630

FASEB J. 2026 May 15. 40(9): e71830

The E3 Ligase RNF8 Promotes Ubiquitination and Degradation of ChREBPα During Liver Stress Response.

Yuee Zhao, Sujuan Wang, Jian Zhang, Sarah Cooke, Gary Zhang, Zifeng Zhao, Joon Oh, Xin Tong, Lei Yin.

As the most common chronic liver disease, MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH) driven by accumulated metabolic and inflammatory stresses. We previously reported that liver ChREBPα protein is markedly downregulated in mouse models of diet-induced MASH and hepatotoxin-induced liver injury. Yet the impact of stress pathways on hepatocyte ChREBPα proteolysis has not been examined. Here, we show that a combined metabolic (palmitate, PA) and inflammatory (TNFα) stress signal promotes ubiquitination and proteasome-mediated degradation of ChREBPα in hepatocytes. More importantly, we identify the stress-induced E3 ligase RNF8 as interacting with and promoting ChREBPα ubiquitination and degradation in a JNK2-dependent manner. In vivo, acute depletion of JNK2 or RNF8 stabilizes ChREBPα in mouse liver, increases some but not all ChREBPα transcriptional targets, and reduces diet-induced liver steatosis, inflammation, and fibrosis. Overall, our findings reveal the biochemical machinery underlying stress-induced ChREBPα proteolysis and suggest that targeting RNF8-mediated ChREBPα ubiquitination could be a new strategy for treating MASH.

DOI: https://doi.org/10.1096/fj.202600106R

bioRxiv. 2026 Apr 14. pii: 2026.04.10.717554. [Epub ahead of print]

Discovery and Preclinical Validation of a Clinically Optimized Mitochondrial Complex I Modulator for Alzheimer's Disease.

Sergey Trushin, Thi Kim Oanh Nguyen, Mark Ostroot, Alexander Galkin, Toshihiko Nambara, Wenyan Lu, Takahisa Kanekiyo, Graham Johnson, Eugenia Trushina.

Alzheimer's disease (AD) is characterized by diminished capacity to mount adaptive cellular stress responses required to maintain energy homeostasis and proteostasis. An emerging therapeutic strategy is to restore adaptive stress responses by inducing mild energetic stress through inhibition of mitochondrial complex I (mtCI). However, pharmacological inhibition of the respiratory chain has remained challenging, as it can induce bioenergetic failure rather than beneficial signaling. Here, we describe C273, a brain-penetrant small molecule that delivers controlled, weak attenuation of mtCI activity to therapeutically restore endogenous adaptive stress pathways. This work establishes a first-in-class mechanism in which calibrated activation of multifaceted adaptive mechanisms enhances cellular resilience, rather than impairing mitochondrial function. Structure-activity relationship optimization yielded a compound with high potency against Aβ-induced cellular toxicity, strong selectivity for mtCI, and favorable drug-like properties. C273 demonstrated excellent oral bioavailability, metabolic stability in mouse, rat, and human microsomes, minimal CYP liabilities, and a clean ancillary pharmacology profile in the Eurofins CEREP44 panel. In vivo , C273 readily crosses the blood-brain barrier and activates AMP-activated protein kinase (AMPK), initiating a coordinated hormetic response characterized by enhanced antioxidant defenses, suppression of inflammatory signaling, induction of autophagy, and increased mitochondrial biogenesis and turnover. Genetic deletion of AMPKα1/α2 abolished these responses, establishing AMPK as a critical mediator of C273 activity. Pharmacological competition experiments further confirmed the target, as pretreatment with non-toxic concentrations of rotenone blocked C273 interaction with the quinone-binding site of mtCI and eliminated its neuroprotective effects. Repeated oral administration of C273 (20-80 mg/kg/day) to wild-type mice for one month produced no detectable cardiac or hepatic toxicity, indicating a favorable in vivo safety margin. Importantly, C273 activated these mechanisms and reduced Aβ and p-Tau levels in induced pluripotent stem cell-derived cerebral organoids from patients with sporadic AD. Collectively, these results establish controlled mtCI modulation as a therapeutic strategy and position C273 as a promising disease-modifying candidate for AD.

DOI: https://doi.org/10.64898/2026.04.10.717554

Am J Physiol Lung Cell Mol Physiol. 2026 Apr 30.

Beyond the Epithelium: Multicellular Niches in Lung Regeneration and Disease.

Sinem Koc-Gunel, Amy L Ryan, Rob E Hynds, Jaymin J Kathiriya.

Pulmonary homeostasis and regeneration require coordination between epithelial cells, immune populations, vascular networks, extracellular matrix, and stromal cells. This mini review examines recent advances in lung niche biology that were a focus of the 2025 Stem Cells, Cell Therapy and Bioengineering in Lung Biology and Diseases Conference. Here we emphasize the impact of non-epithelial compartments essential for tissue function and repair. Reflecting the conference's emphasis on comprehensive niche biology, we highlight how non-epithelial compartments, including stromal, vascular, and immune cells, serve as essential regulators of tissue function and repair, a perspective that unified many of the presentations and discussions. In diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease, disruption of these niche interactions, rather than isolated cellular defects, drives regenerative failure. Spatial transcriptomic approaches reveal how pathological cell states colocalize within aberrant micro-niches. These insights suggest that effective therapeutics must target entire multicellular ecosystems, with advanced organoid platforms offering promising tools for developing niche-modulating interventions.

Keywords: Airway; Extracellular Matrix; Mechanosensing; Micro-niches; Stem Cells

DOI: https://doi.org/10.1152/ajplung.00419.2025

bioRxiv. 2026 Apr 13. pii: 2026.04.10.717808. [Epub ahead of print]

The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice.

Alicia A Cutler, Tenaya K Vallery, Thomas O Vogler, Jesse Kurland, Thea S Zlatklov, Tiffany Antwine, Nicole Dalla Betta, Tze-Ling Chang, Brad Pawlikowski, Carson H Butcher, Kory J Lavine, David M Ornitz, Kristi S Anseth, Bradley B Olwin.

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

DOI: https://doi.org/10.64898/2026.04.10.717808

Cells. 2026 Apr 09. pii: 662. [Epub ahead of print]15(8):

Dysregulated Repair in Aging and Disease: Extracellular Vesicles as an Emerging Protective Strategy.

Anna Calabrò, Giulia Accardi, Alexander Batista-Duharte, Mattia Emanuela Ligotti, Alejandra Pera, Chiara Puleo, Maurizio Soresi, Giuseppina Candore, Anna Aiello.

Tissue repair is a finely organized process that progresses via a series of phases, including hemostasis, inflammation, proliferation, and remodeling, which are coordinated by immune-stromal interactions. Aging profoundly dysregulates these processes through mechanisms such as immunosenescence and inflammaging, cellular senescence, chronic inflammation, and extracellular matrix alterations, ultimately contributing to typical age-related progression. This review discusses the immune mechanisms that govern physiological tissue healing, as well as the age-related perturbations that lead to ulcerative and fibrotic diseases. It also highlights the potential application of extracellular vesicles (EVs), both mammalian and plant-derived, as a stable and low-immunogenicity mediator to modulate and re-establish repair homeostasis. Translational hurdles such as EV standardization, dosing, safety assessment, and manufacturing are critically discussed to promote their use in geroscience, regenerative medicine, and dermatology.

Keywords: extracellular vesicles; fibrosis; healing; immune system; immunosenescence; regenerative medicine; tissue repair; ulceration; wound healing–fibrosis–cancer

DOI: https://doi.org/10.3390/cells15080662