bims-mihora 2026-02-15 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–02–15
eight papers selected by
Lisa Patel, Istesso

Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer's disease.
Mitochondrial presequences are more than just address labels.
Luteolin use in Integrated Stress Response: insight from a case of EIF2AK2-related dystonia.
Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.
Overloaded mitochondrial stress drives reproductive damage in GC-1 mouse spermatogonia cells exposed to nickel nanoparticle.
Effects of Mechanical Stress on Bone and Cartilage Metabolism: How Mechanical Stress Affects Energy Metabolism in Bone and Cartilage Tissues (Our Research Overview): Mini Review.
Enhancing Astronaut Resilience: The Role of Elevated ROS in Adapting to Space Radiation.

Front Cell Dev Biol. 2025 ;13 1699206

Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.

Fasih A Rahman, Joe Quadrilatero.

  Aging impairs the regenerative capacity of skeletal muscle in part through the functional decline of the resident stem cell population called satellite cells. With age, satellite cells exhibit a loss of quiescence, altered proliferation, and impaired differentiation, leading to incomplete myogenesis following injury. Mitochondria are central to stem cell function, providing ATP, regulating redox homeostasis, and integrating several signaling pathways during lineage progression. While mitochondrial remodeling and function is essential for supporting the metabolic demands of myogenesis, the extent to which these processes are altered in aged satellite cells across cell states remains unclear. To address this, we performed a comparative transcriptomic analysis of young and aged satellite cells in quiescent, proliferating, and early differentiating states using three publicly available microarray datasets. Our results reveal that aged satellite cells exhibit a dysregulated senescence profile, characterized by the simultaneous upregulation of both senescence-inducing and -inhibiting genes, suggestive of a metastable senescence state. These features persisted during early differentiation, where aged cells also displayed increased expression of senescence-associated secretory phenotype (SASP) components, potentially contributing to a pro-inflammatory niche. Mitochondrial gene expression was relatively stable in quiescent cells but showed marked remodeling upon activation, particularly in aged cells. While young satellite cells upregulated transcriptional programs related to mitochondrial function, aged cells exhibited broader and less coordinated responses enriched for stress, apoptotic, and metabolic pathways. Despite evidence of mitochondrial stress, mitophagy gene activation remained limited in aged cells, raising the possibility of impaired organelle quality control. Together, our findings highlight age-associated disruptions in both senescence and mitochondrial remodeling programs across the satellite cell lifecycle. These transcriptional changes likely underlie impaired regenerative responses in aging muscle and identify potential targets for rejuvenating muscle stem cell function.

Keywords:  SASP; aging; mitochondrial remodeling; satellite cell; senescence; skeletal muscle; skeletal muscle regeneration

DOI:  https://doi.org/10.3389/fcell.2025.1699206
Genes Dis. 2026 May;13(3): 101846

Three-dimensional interactive network: Mitochondrial-metabolic-calcium homeostasis driving Alzheimer's disease.

Tingting Liu, Zongting Rong, Jingwen Li, Haojie Wu, Jianshe Wei.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a "pathological triad"-mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad's vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.

Keywords:  Alzheimer’s disease; Calcium homeostasis imbalance; Metabolic dysregulation; Mitochondrial dysfunction; Molecular mechanisms

DOI:  https://doi.org/10.1016/j.gendis.2025.101846
Protein Sci. 2026 Mar;35(3): e70491

Mitochondrial presequences are more than just address labels.

Erik Marcel Heller, Svenja Lenhard, Doron Rapaport, Johannes Herrmann.

  Most mitochondrial proteins are synthesized in the cytosol as precursor proteins with N-terminal presequences. These presequences serve as targeting signals that facilitate the binding to mitochondrial surface receptors and translocation across the mitochondrial membranes. However, recent studies showed that presequences can be more than address tags. They can contain degradation signals recognized by components of the ubiquitin-proteasome system, and therefore, serve as timers that determine the lifespan of newly synthesized precursor proteins. Moreover, presequences can interact with components of the cytosolic chaperone system to prevent or delay precursor folding. Finally, presequences of some dually localized proteins contain targeting information not only for mitochondria but also for other cellular destinations such as the nuclear lumen or chloroplasts in plant cells. Thus, presequences contain multifaceted information to endow mitochondrial precursor proteins with specific properties that are critical for the early steps of mitochondrial protein biogenesis.

Keywords:  Presequence; chaperones; mitochondria; proteasome; protein import; ubiquitin ligases

DOI:  https://doi.org/10.1002/pro.70491
Eur J Paediatr Neurol. 2026 Feb 05. pii: S1090-3798(26)00004-8. [Epub ahead of print]60 109-113

Luteolin use in Integrated Stress Response: insight from a case of EIF2AK2-related dystonia.

Antonio Spagarino, Luca Urru, Miryam Rosa Stella Foti, Marianna Farnè, Elisa Pisaneschi, Stefania Bigoni, Cristina Forest, Agnese Suppiej.

  This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections, is associated with disruptions in the integrated stress response (ISR). The ISR, a cellular signaling pathway activated in response to stress, culminates in the phosphorylation of eIF2α, which modulates protein synthesis and can induce cell death. Pathogenic variants in EIF2AK2 disrupt this pathway, contributing to the development of dystonia. Luteolin, a flavonoid possessing anti-inflammatory and neuroprotective properties, was hypothesized to modulate the ISR, thereby attenuating infection-induced dystonic exacerbations. The patient, exhibiting early-onset dystonia with clinical worsening during febrile episodes, harbored a de novo pathogenic variant in EIF2AK2. Following initial clinical improvement with trihexyphenidyl, adjunctive luteolin therapy was initiated, resulting in further clinical enhancements. Quantitative assessment using dystonia rating scales (UDRS, MSS, DSS) demonstrated sustained improvement, characterized by a reduction in the severity and frequency of infection-triggered relapses. The proposed mechanism of action involves luteolin disrupting the PACT-PKR interaction, a critical step in ISR activation, thus preventing excessive eIF2α phosphorylation and subsequent cellular dysfunction. This mechanism, supported by in vitro studies utilizing relevant disease models, suggests luteolin's potential to stabilize cellular homeostasis under stress. This case report indicates that luteolin may serve as a promising adjunctive therapeutic strategy for patients with infection-sensitive dystonic phenotypes, such as EIF2AK2-related dystonia. Further randomized controlled trials are warranted to validate these findings and establish the optimal dosing regimen and long-term safety profile of luteolin in vivo.

Keywords:  Dystonia; EIF2AK2; Integrated stress response; Luteolin

DOI:  https://doi.org/10.1016/j.ejpn.2026.02.001
Autophagy. 2026 Feb 12. 1-3

Mitophagy bridges glucose metabolism, inflammation and neuroprotection in astrocytes.

Hanna Hakansson, Jack H Howden, Josef T Kittler.

  Mitochondria regulate ATP production, calcium buffering, and apoptotic signaling, and clearing dysfunctional mitochondria by mitophagy is essential for cellular homeostasis. While PINK1-dependent mitophagy is well-characterized in neurons, its function in glial cells such as astrocytes is less understood. Our study demonstrates that PINK1-mitophagy in astrocytes occurs faster and with less spatial restriction compared to neurons. This pathway was specifically regulated in astrocytes by the glycolytic enzyme, HK2 (hexokinase 2), which forms a glucose-dependent complex with PINK1 following mitochondrial damage. Inflammation also induces HK2-PINK1 mitophagy, and its activation in astrocytes protects against cytokine-induced neuronal death. Our findings characterize a novel HK2-PINK1 pathway in astrocytes that bridges mitophagy, metabolism, and immune signaling.Abbreviation: HK2: hexokinase 2; PD: Parkinson disease; PINK1: PTEN induced kinase 1; S65: serine 65.

Keywords:  Astrocyte; HK1; PINK1; mitochondria; mitophagy; neurodegeneration; parkin

DOI:  https://doi.org/10.1080/15548627.2026.2623987
Cell Biol Toxicol. 2026 Feb 11.

Overloaded mitochondrial stress drives reproductive damage in GC-1 mouse spermatogonia cells exposed to nickel nanoparticle.

Lu Kong, Geyu Liang, Yán Wāng.

  Nickel nanoparticles (Ni NPs) are widely used in industrial and commercial sectors, raising concerns about their potential occupational and environmental toxicity. Male infertility has increased significantly in recent decades, with environmental exposures playing a recognized role. Ni NPs have been identified as toxic agents that induce testicular damage and sperm abnormalities, yet their underlying molecular mechanisms are unknown. In this study, mouse spermatogonia GC-1 cells were used as an in vitro model to explore the role of mitochondrial autophagy (mitophagy) in the induced apoptosis of Ni NPs. Ni NPs significantly reduced cell viability, increased intracellular ROS levels, disrupted mitochondrial membrane potential, and triggered germ cell apoptosis. PINK1 and Parkin, key mitophagy-related proteins, exhibited significant upregulation. Cyclosporin A was used to inhibit mitophagy, attenuating mitochondrial damage and reducing apoptosis. In addition, PINK1 knockdown achieved by lentiviral transfection confirmed its critical role in mediating Ni NPs-induced mitophagy and subsequent cell death. These findings demonstrate that overactivation of the PINK1/Parkin pathway promotes apoptosis to Ni NPs exposure by mitophagy. Our study provides new mechanistic insights into the role of mitophagy in reproductive damage caused by nanomaterials.

Keywords:  Apoptosis; Autophagy; Metal nanoparticle; Mitochondrial dysfunction; Reproductive toxicology

DOI:  https://doi.org/10.1007/s10565-026-10153-8
Int J Mol Sci. 2026 Jan 30. pii: 1380. [Epub ahead of print]27(3):

Effects of Mechanical Stress on Bone and Cartilage Metabolism: How Mechanical Stress Affects Energy Metabolism in Bone and Cartilage Tissues (Our Research Overview): Mini Review.

Hideaki Iwata, Satomi Sato, Shu Somemura, Masahiro Takemoto, Yuki Takahashi-Suzuki, Yodo Sugishita, Hiroto Fujiya, Naoki Haraguchi, Kazuo Yudoh.

  Bone resorption and formation are known to change in response to mechanical stress. The mechano-transduction mechanism by which bone tissue senses the stress, altering cellular activity in response via intracellular signaling pathways, ultimately leading to physiological and pathological changes, is beginning to be elucidated. Furthermore, excessive mechanical stress on bone and joints due to aging, obesity, overload, and overuse is thought to cause decreased chondrocyte activity, degeneration and destruction of the cartilage collagen matrix, degeneration of the subchondral bone, and joint dysfunction, contributing to the progression of osteoarthritis (OA). However, much remains unknown about how osteoblasts, responsible for bone formation, and chondrocytes, responsible for cartilage homeostasis, sense and respond to mechanical stress. Furthermore, whether there are mechanisms to protect against pathological and excessive mechanical stress in bone and cartilage tissue, their associated molecular mechanisms, and the relationship between mechanical stress responses and osteochondral degeneration, remain unknown. Understanding these mechanisms is considered essential for the development of new therapeutic strategies for osteochondral diseases. Our research aims to deepen our understanding of the etiology and pathophysiology of bone and cartilage diseases (osteoporosis, fragility fracture, and OA) and to develop new treatments from the perspective of mechanical stress response. In this paper we review the latest findings regarding the roles of cellular energy regulators (glucose transporters and energy sensors) and mechanical stress response factors, and the relationship between these factor-mediated changes in energy metabolism and osteochondral degeneration. This minireview discusses how energy metabolism regulators control the activity of both osteoblasts and chondrocytes in osteochondral tissue in response to mechanical stress.

Keywords:  bone metabolism; cartilage metabolism; chondrocyte; energy metabolism; mechanical stress; mitochondria; osteoblast

DOI:  https://doi.org/10.3390/ijms27031380
J Biomed Phys Eng. 2026 Feb;16(1): 81-84

Enhancing Astronaut Resilience: The Role of Elevated ROS in Adapting to Space Radiation.

Mahsa Pakroo, Seyed Ali Reza Mortazavi, Seyed Mohammad Javad Mortazavi.

  The microgravity environment and high radiation levels in space lead to a significant increase in Reactive Oxygen Species (ROS) production compared to Earth, which can have detrimental effects on astronaut health over time. This study examines the hypothesis that high levels of ROS in living organisms in space may aid pre-selected astronauts' cells in adapting to the intense radiation encountered during missions to Mars and beyond. By looking at evolutionary biology and past radiation events like the Chernobyl disaster, we suggest that increased ROS could trigger adaptive responses similar to those seen in radiation-resistant organisms such as tardigrades. This paper explores the dual nature of ROS as both harmful agents and vital signaling molecules, evaluating their potential to enhance DNA repair, boost antioxidant defenses, and alter mitochondrial metabolism. We aim to see if managing ROS could be a strategy to prepare astronauts' cells for space travel, using cytogenetic tests to find individuals with strong adaptive responses.

Keywords:   Adaptation; Astronauts; Microgravity; Radiation; Reactive Oxygen Species; Space

DOI:  https://doi.org/10.31661/jbpe.v0i0.2407-1791