bims-mihora 2026-04-12 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–04–12
nine papers selected by
Lisa Patel, Istesso

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.
Mitochondria transfer in tissue homeostasis and diseases.
Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.
Dysplastic Epithelial Repair Propagates Chronic Pathology Through the Paracrine Transformation of Pulmonary Fibroblasts.
Role of stem cells in articular cartilage repair - a narrative review.
Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.
Regenerative and Repair Roles of Alveolar Epithelial Cells Following Lung Injury.
Bioinspired, Mitochondria-Targeted Single-Atom Nanozyme Enhances Bone Regeneration by Reprogramming Stem Cell Energy Metabolism.

Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
Free Radic Biol Med. 2026 Apr 06. pii: S0891-5849(26)00266-2. [Epub ahead of print]

Mitochondria Transplantation Preserves Retinal Ganglion Cells and Promotes CNS Axonal Regeneration.

Ajay Ashok, Kin-Sang Cho, Wai Lydia Tai, Lu Huang, Hio Tong Kam, Suman Chaudhary, Karen Chang, Sarita Pooranawattanakul, Julie Chen, Anton Lennikov, Dong Feng Chen.

  Mitochondrial dysfunction is a central driver of retinal ganglion cell (RGC) loss in glaucoma and other forms of optic neuropathies, leading to irreversible blindness. Here, we demonstrate that replenishing the mitochondrial pool through exogenous mitochondrial transplantation ("mitotherapy") in adult mice not only preserves neuronal survival but also promotes regenerative competence in the central nervous system (CNS). In aging or injured RGCs, we identified profound deficits in mitochondrial biogenesis, fission-fusion balance, and mitophagy. Transplantation of functional mitochondria in in vitro models of trophic deprivation and glutamate excitotoxicity restored mitochondrial homeostasis, improved energy production, reduced reactive oxygen species, enhanced RGC survival, and drove robust neurite outgrowth, with transplanted mitochondria actively trafficking to growth cones. This effect was dampened following inhibition of mitochondrial fusion indicating a pivotal role of fusion-dependent functional integration of exogenous mitochondria. Strikingly, intravitreal delivery of mitochondria in an optic nerve crush model of adult mice enabled their integration into RGCs, improved survival and electrophysiological responses, and supported axonal regeneration across the lesion site. These findings indicate that mitochondrial transplantation strategy rescues bioenergetic failure and supports a pro-regenerative activity of neurons, highlighting the potential of mitotherapy as a transformative approach for neurodegenerative eye diseases and CNS injuries.

Keywords:  Mitochondrial transplantation; PC12 cells; SH-SY5Y cells; nerve regeneration; neuroprotection; optic nerve crush; retinal ganglion cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.069
Int J Biol Sci. 2026 ;22(6): 3144-3173

Mitochondria transfer in tissue homeostasis and diseases.

Lei Qin, Donghao Gan, Zecai Chen, Zhen Xu, Mingyue Wu, Bimin Gao, Yufeng Long, Xihong Mou, Wenqing Li, Weihong Yi, Guozhi Xiao.

  Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria are segregated and transported from parent to daughter cells during division or differentiation, a process known as vertical mitochondria transfer (VMT). A growing body of literature indicates that various cell types can export mitochondria for delivery to developmentally unrelated cell types without division, a process termed horizontal mitochondria transfer (HMT). In this review, we summarize current understanding of the modes of mitochondria transfer and illustrate the phenomenon of HMT across different tissue backgrounds, including the immune, cardiovascular, respiratory, hepatic, renal, musculoskeletal, adipose, and reproductive systems. Moreover, updated applications and functions of mitochondria transfer are discussed. Additionally, we also highlight the therapeutic potential of mitochondria transfer in current preclinical and clinical trials for inherited mitochondrial diseases, cancer, wound healing, and injuries of the respiratory and central nervous systems.

Keywords:  extracellular vesicles (EVs); gap junctions (GJs); horizontal mitochondria transfer; intercellular mitochondria transfer; tunneling nanotubes (TNT); vertical mitochondria transfer

DOI:  https://doi.org/10.7150/ijbs.129709
Front Cell Dev Biol. 2026 ;14 1720480

Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.

Jian Yue, Tianyi Pu, Dele He, Yangyong Luo, Simin Ruan, Huahan Li, Jianwei Zhan, Guosen Su, Jianyuan Su, Sheng Chen, Guoxing Huang.

  Immunotherapy resistance remains a major obstacle in treating breast cancer, particularly aggressive subtypes like triple-negative breast cancer (TNBC). This review delineates the pivotal role of the Integrated Stress Response (ISR) as a central metabolic-immune regulator driving this resistance. The ISR is activated in the tumor microenvironment (TME) by diverse stressors-including hypoxia, nutrient scarcity, and ER stress-via four upstream kinases (PERK (PKR-like ER kinase), GCN2, PKR, HRI). These kinases converge to phosphorylate eukaryotic initiation factor 2α (eIF2α), leading to the selective translation and robust activation of the transcription factor ATF4. The ensuing ATF4-driven program fosters an immunosuppressive TME through multifaceted mechanisms: tumor-intrinsic upregulation of PD-L1, secretion of immunosuppressive exosomes, metabolic reprogramming that depletes critical amino acids, and direct impairment of T cell function and antigen presentation. Concurrently, ISR activation in immune cells-such as myeloid-derived suppressor cells (MDSCs) and dendritic cells-further dampens antitumor immunity. Targeting the ISR with small-molecule inhibitors (PERK or GCN2 inhibitors, ISRIB) or repurposed agents (metformin) demonstrates compelling preclinical efficacy in reversing immunosuppression and synergizing with immune checkpoint inhibitors. Biomarker-driven strategies, including ISR gene signatures and p-eIF2α immunohistochemistry, offer promising avenues for patient stratification. Thus, pharmacological targeting of the ISR represents a strategically viable approach to reprogram the immunosuppressive TME and overcome immunotherapy resistance in breast cancer, warranting urgent clinical investigation.

Keywords:  breast cancer; eIF2α-ATF4 axis; immune checkpoint inhibitors; immunotherapy resistance; integrated stress response (ISR); tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2026.1720480
bioRxiv. 2026 Apr 05. pii: 2026.04.02.716135. [Epub ahead of print]

Dysplastic Epithelial Repair Propagates Chronic Pathology Through the Paracrine Transformation of Pulmonary Fibroblasts.

Nicolas P Holcomb, Ronel Z Samuel, Alena Klochkova, Joanna Wong, Sara Kass-Gergi, Meryl Mendoza, Michael M Maiden, Evelyn A Martinez, Diana M Abraham, Madeline Singh, Harshini Kelam, Jarod A Zepp, Andrew E Vaughan.

Severe lung injury promotes the ectopic accumulation of basal cells in the alveoli and the presence of these dysplastic epithelial cells are strongly associated with regions of pulmonary fibrosis (PF) in diseased lungs. Recent studies have identified a unique subset of "inflammatory" fibroblasts expressing pro-inflammatory genes, especially cytokines involved in monocyte recruitment, that are also enriched in disease and thought to contribute to the onset and progression of PF. Here we show that these two injury-induced cell types are intricately connected, in that dysplastic basal cells generate diffusible signals to robustly induce the inflammatory phenotype in pulmonary fibroblasts. Capitalizing on transcriptomic analysis, we identify the enriched inflammatory signaling pathways in treated fibroblasts and specifically demonstrate that IL-1α secreted by dysplastic basal cells is responsible for this fibroblastic transformation. IL-1α neutralization in vivo is sufficient to significantly reduce the inflammatory fibroblast burden in regions of alveolar bronchiolization, and the resolution of inflammatory fibroblasts in turn reduces CCR2+ immune cell recruitment to these areas. These results suggest dysplastic basal cells play an indirect role in chronic inflammation and fibrotic remodeling through the induction of a proinflammatory fibroblast phenotype and subsequent recruitment of immune cells, establishing a chronic wound healing microenvironment that prolongs localized pathologic remodeling.

DOI: https://doi.org/10.64898/2026.04.02.716135
Wiad Lek. 2026 ;79(3): 553-557

Role of stem cells in articular cartilage repair - a narrative review.

Jakub Kot, Kacper Lee, Zeeshan Zulfiqar, Julia Zjawiony, Mateusz Kaczmarski, Silvija Ille.

  Articular cartilage injuries pose a major clinical obstacle due to their inability to regenerate contributed by cartilages' intrinsic properties and close association with osteoarthritis and progressive joint degeneration. Cartilage damage may be a consequence of acute trauma, repeated mechanical overload or age-related degenerative processes which often leads to chronic pain, joint dysfunction and a deterioration in the quality of life of patients.Established treatments such as; conservative management, intra-articular drug administrations and surgical cartilage repair typically provide relief. However, it's important to note that these treatments rarely lead to complete, permanent regeneration of natural hyaline cartilage. Recently, regenerative medicine has been paying significant attention to stem cell therapies. It aims to support cartilage repair while simultaneously impacting the intra-articular environment. It's safe to say that these approaches are increasingly being considered as potential therapeutic methods. Between the various cell populations, mesenchymal cells have gained particular attention due to their ability to promote chondrogenic differentiation, immunomodulatory properties, and paracrine effects.There is growing evidence suggesting that stem cells effects can be mediated not only by direct source replacement but are also contributed by the secretion of bioactive factors that influence physical processes, cartilage metabolism, and endogenous repair mechanisms. This narrative review aims to concisely summarize and critically evaluate novel evidence and scientific data on the biological repair mechanisms, clinical outcomes and safety assessment of stem cell-based therapies used to treat articular cartilage repair.

Keywords:   hyaline cartilage ; knee osteoarthritis ; regenerative medicine

DOI:  https://doi.org/10.36740/WLek/218174
Ageing Res Rev. 2026 Apr 07. pii: S1568-1637(26)00123-6. [Epub ahead of print] 103131

Mitochondria-associated endoplasmic reticulum membranes as aging-sensitive signaling hubs in degenerative musculoskeletal diseases.

Linbo Peng, Kexin Wang, Limin Wu, Lei Yao, Bin Shen, Jian Li.

  Degenerative musculoskeletal diseases (DMDs), including osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration, are highly prevalent age-related conditions characterized by progressive tissue dysfunction and loss of musculoskeletal integrity. Aging is accompanied by profound alterations in organelle homeostasis, metabolic signaling, and stress adaptation, among which mitochondria-endoplasmic reticulum communication has emerged as a critical regulatory axis. Mitochondria-associated membranes (MAMs) are specialized contact sites that spatially and functionally couple the endoplasmic reticulum and mitochondria, thereby coordinating calcium signaling, redox balance, lipid metabolism, and cell fate decisions. Accumulating evidence indicates that aging-related disruption of MAMs integrity and signaling contributes to mitochondrial dysfunction, oxidative stress, aberrant stress responses, and inflammatory activation across multiple musculoskeletal tissues. In this review, we synthesize current evidence linking MAMs-associated signaling pathways-including calcium flux, reactive oxygen species regulation, unfolded protein response signaling, autophagy, inflammasome activation, and regulated cell death-to the pathogenesis of major degenerative musculoskeletal diseases. We further highlight shared and tissue-specific mechanisms through which age-dependent MAMs dysregulation drives musculoskeletal degeneration. By framing MAMs as aging-sensitive signaling hubs, this review provides an integrated perspective on how organelle crosstalk contributes to degenerative musculoskeletal diseases and identifies conceptual frameworks for understanding disease convergence during musculoskeletal aging.

Keywords:  Calcium homeostasis; Degenerative musculoskeletal diseases; ER–mitochondria crosstalk; Mitochondria-associated ER membranes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.arr.2026.103131
Am J Physiol Lung Cell Mol Physiol. 2026 Apr 10.

Regenerative and Repair Roles of Alveolar Epithelial Cells Following Lung Injury.

Akira Yamagata, Anthea Weng.

The alveolar epithelium, composed of type 1 (AT1) and type 2 (AT2) cells, is central to gas exchange and the lung's response to injury. Historically viewed as a simple barrier, recent advances have unveiled the profound dynamics and plasticity of these cells in orchestrating tissue repair. This mini-review synthesizes recent breakthroughs in our understanding of the cellular and molecular mechanisms governing alveolar regeneration. We focus on the expanding diversity of progenitor cells, including resident AT2 cells and newly identified multipotent progenitors in the distal airways, and the complex signaling networks that dictate their fate. Furthermore, we explore the emergence of transitional cell states during repair and how aberrant cellular behaviors can drive pathological outcomes like fibrosis. A deeper comprehension of this dynamic cellular behavior is paramount for developing novel therapeutic strategies to promote effective lung repair and combat chronic lung disease.

DOI: https://doi.org/10.1152/ajplung.00421.2025
Adv Mater. 2026 Apr 07. e22108

Bioinspired, Mitochondria-Targeted Single-Atom Nanozyme Enhances Bone Regeneration by Reprogramming Stem Cell Energy Metabolism.

Yuwen Wang, Xinzhi Liang, Tiandi Xiong, Zheng Zhong, Ning Zhang, Boguang Yang, Dong Li, Qiongjiao Zeng, Xian Chen, Yiting Lei, Shangsi Chen, Chao Zheng, Liu Yang, Wei Huang, Rocky S Tuan, Denghui Xie, Zhong Alan Li.

  Normal mitochondrial function in stem cells is essential for effective bone regeneration, with mitochondrial complex IV (cytochrome c oxidase, CcO) playing a crucial role in sustaining electron transport chain activity and ATP synthesis. To address mitochondrial dysfunction associated with bone defects, we developed a dendritic mesoporous silica nanoparticle (DMSN)-based, CcO-mimetic nanozyme, named triphenylphosphonium (TPP)-DMSN-Fe/Cu. The nanozyme incorporated iron and copper single atoms to mimic the catalytic center of CcO and is modified with the mitochondria-targeting agent TPP. In vitro, TPP-DMSN-Fe/Cu nanozymes colocalized with mitochondria and enhanced mitochondrial function, effectively regulating cellular energy metabolism and promoting stem cell osteogenesis. In vivo, TPP-DMSN-Fe/Cu nanozymes resulted in significantly enhanced bone regeneration compared to the control, resulting in a 177% increase in bone volume and a 12% increase in mineral density at critical-sized bone defects in rats after 4 weeks of treatment. Taken together, these findings demonstrate that bioinspired, mitochondria-targeting TPP-DMSN-Fe/Cu nanozymes hold strong promise for accelerating bone regeneration via regulating cellular energy metabolism.

Keywords:  bone regeneration; mitochondrial energy metabolism; nanoparticles; osteogenic differentiation; stem cells

DOI:  https://doi.org/10.1002/adma.202522108