bims-mihora 2026-05-17 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–05–17
eleven papers selected by
Lisa Patel, Istesso

Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.
Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.
ATF4: Orchestrating Cellular Stress Adaptation, Metabolism, and Immune Regulation in Health and Disease.
Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
Type 2A fibers exhibit higher mitochondrial content than type 1 fibers in mouse skeletal muscles across physiological conditions.
Mitochondria as an Integrative Hub of Cellular Homeostasis and Stress Response.
The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.
Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.
170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.
The complex mechanistic network of periprosthetic osteolysis: Integration from inflammatory response and tissue stress to signaling pathways.

Bioessays. 2026 May;48(5): e70146

Mitochondrial Signaling and Stress Responses, Key Regulators of Aging and Longevity.

Yi Sheng, Zachary Markovich, Sung Min Han, Rui Xiao.

  Mitochondria are vital not only for energy production but also for regulating signaling pathways that influence aging. While mitochondrial dysfunction contributes to age-related decline, emerging evidence shows that mild, regulated mitochondrial stress can paradoxically promote longevity. This review highlights recent advances in mitochondrial biology and aging across species. We explore the dual role of reactive oxygen species (ROS) as both damaging agents and signaling molecules that activate adaptive stress responses. Key pathways such as the mitochondrial unfolded protein response (UPRMT) and integrated stress response (ISR) are discussed, including their tissue-specific as well as non-cell-autonomous effects on aging. Additionally, we examine the impact of mitochondrial protein import/export, dynamics (fission, fusion, mitophagy, biogenesis), and quality control in aging. Finally, we address challenges in understanding context-dependent mitochondrial responses and mitonuclear communication. Together, these insights position mitochondria as central regulators of aging and highlight their potential as therapeutic targets to enhance health span and longevity.

Keywords:  aging; integrated stress response; mitochondria ROS; mitochondrial dynamics; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1002/bies.70146
Am J Physiol Cell Physiol. 2026 May 13.

Divergent mitochondrial stressors elicit specific retrograde signaling pathways in muscle myotubes.

Klaudia Sztolsztener, Thulasi Mahendran, David A Hood.

  Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.

Keywords:  integrated stress response; mitochondrial biogenesis; mitochondrial proteostasis; mitochondrial unfolded protein response; muscle contractile activity

DOI:  https://doi.org/10.1152/ajpcell.00167.2026
Int J Mol Sci. 2026 Apr 24. pii: 3784. [Epub ahead of print]27(9):

ATF4: Orchestrating Cellular Stress Adaptation, Metabolism, and Immune Regulation in Health and Disease.

Chunyan Wang, Fengjing Jia, Feng He.

  Activating transcription factor 4 (ATF4) is a master transcription factor of integrated stress response (ISR), an evolutionarily conserved intracellular signaling network that helps the cell, tissue, and organism to adapt to various unpredictable environmental fluctuations, mitigate the challenges, and maintain health. Stress-induced ATF4 expression regulates a wild variety of gene expression programs to enable stress management and repair for cell homeostasis and integrity. However, chronic ATF4 activation contributes to pathologies including cancer, inflammation, and neurodegeneration. Extensive studies have revealed that ATF4 regulates many cellular processes including autophagy, apoptosis, metabolism, and inflammation. Emerging evidence has uncovered new signaling pathways in regulation of ATF4 expression and activation, including at transcriptional, translational, and post-translational levels, and new functions of ATF4 in the progression of various metabolic and stress-related diseases, including inflammation, cancer, and cardiovascular disease. The diversity of ATF4 functions is increasingly appreciated. This review summarizes the recent findings of the complex regulatory network of ATF4 activity and its roles in integrating stress responses, metabolic reprogramming, unfolded protein responses, autophagy, inflammation, and immunity.

Keywords:  ATF4; endoplasmic reticulum; integrative stress response; unfolded protein response

DOI:  https://doi.org/10.3390/ijms27093784
Mech Ageing Dev. 2026 May 08. pii: S0047-6374(26)00043-6. [Epub ahead of print]231 112191

Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.

YiFan Yan, Yuetong Li, Heng Ma.

  Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.

Keywords:  Aging; Lysosome; Membrane contact sites; Mitochondria-lysosome contacts; Mitochondrial quality control; Organelle homeostasis

DOI:  https://doi.org/10.1016/j.mad.2026.112191
Biochem Biophys Res Commun. 2026 Jul 09. pii: S0006-291X(26)00674-1. [Epub ahead of print]821 153910

Type 2A fibers exhibit higher mitochondrial content than type 1 fibers in mouse skeletal muscles across physiological conditions.

Eiji Wada, Nao Susumu, Kotaro Ariga, Yukiko K Hayashi.

  Skeletal muscle is composed of a heterogeneous mixture of oxidative slow-twitch type 1 fibers and glycolytic fast-twitch type 2 fibers (2A, 2XD, and 2B), defined by their myosin heavy chain isoform. Among the defining characteristics of muscle fiber types, a high mitochondrial content is classically associated with type 1 fibers in human skeletal muscles. In addition, mitochondrial adaptations occur according to the energy demands of each fiber type. In contrast, type 1 fibers exhibit lower mitochondrial enzyme activities than type 2A fibers in rodent limb muscles, and fiber type-specific adaptation of mitochondrial content in rodent models remains unclear. In this study, we comprehensively examined mitochondrial content at the single-myofiber level across multiple muscle regions in mice and investigated fiber type-dependent changes of mitochondrial content under various physiological conditions. We demonstrate that type 2A fibers possess higher mitochondrial content than type 1 fibers across different skeletal muscle regions in mice. Importantly, this relationship was maintained under different physiological conditions, including aging and exercise. In addition, our study identified type 2XD fibers as a metabolically plastic population that responds dynamically to physiological stimuli. These findings suggest that mitochondrial content in each skeletal muscle isotype is both species-specific and context-dependent.

Keywords:  Mitochondrial adaptation; Mitochondrial content; Mouse skeletal muscle; Muscle fiber type; SDH and COX staining; Single myofiber

DOI:  https://doi.org/10.1016/j.bbrc.2026.153910
Int J Mol Sci. 2026 Apr 27. pii: 3871. [Epub ahead of print]27(9):

Mitochondria as an Integrative Hub of Cellular Homeostasis and Stress Response.

Valentina Mihaylova, Eleonora Kovacheva, Maria Gevezova, Victoria Sarafian, Maria Kazakova.

  Mitochondria are increasingly recognized as multifunctional organelles that integrate metabolic, redox, immune, and cell fate signaling, thereby maintaining cellular and tissue homeostasis under physiological conditions. Beyond their classical role in ATP production, mitochondria act as central regulatory hubs coordinating adaptive responses to metabolic demands and environmental stress. These functions are sustained through tightly regulated quality control mechanisms, including mitochondrial biogenesis, dynamic fusion-fission remodeling, redox signaling, and selective removal of damaged organelles via mitophagy. Disruption of these processes compromises cellular resilience and contributes to disease initiation and progression. This review summarizes and critically evaluates current evidence on mitochondrial function in health and its dysregulation in pathological conditions, with a particular focus on rheumatoid arthritis (RA), ischemic stroke (IS), and autism spectrum disorder (ASD). Despite their distinct clinical manifestations, these disorders share convergent mitochondrial abnormalities, including metabolic reprogramming toward glycolysis, excessive or persistent reactive oxygen species production, impaired mitophagy, mitochondrial DNA-driven innate immune activation, and hypoxia-related stress. In RA, mitochondrial dysfunction sustains chronic inflammation and joint destruction; in IS, acute mitochondrial failure and reperfusion-associated oxidative stress drive neuronal injury; and in ASD, mitochondrial metabolic inflexibility and defective quality control contribute to chronic low-grade inflammation and neurodevelopmental vulnerability. A variety of methods for the assessment of mitochondrial function are available to study these pathological conditions. Collectively, these findings position mitochondrial dysfunction as a unifying pathogenic mechanism linking inflammatory, neurodegenerative, and neurodevelopmental processes. Targeting mitochondrial metabolism, redox balance, and quality control pathways therefore represents a promising cross-disease therapeutic strategy.

Keywords:  autism spectrum disorder; ischemic stroke; mitochondrial function; rheumatoid arthritis

DOI:  https://doi.org/10.3390/ijms27093871
Aging Cell. 2026 05;25(5): e70534

The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.

Prasanna Katti, Praveena Prasad, Sepiso K Masenga, Prasanna Venkhatesh, Zer Vue, Andrea G Marshall, Benjamin Rodriguez, Han Le, Edgar Garza-Lopez, Alexandria Murphy, Brenita Jenkins, Ashlesha Kadam, Jianqiang Shao, Amber Crabtree, Pamela Martin, Chantell Evans, Mark A Phillips, David Hubert, Nelson Wandira, Okwute M Ochayi, Dhanendra Tomar, Clintoria R Williams, Jennifer Gaddy, Briar Tomeau, LaCara Bell, Taneisha Gillyard, Markis' Hamilton, Vineeta Sharma, Mohd Mabood Khan, Elma Zaganjor, Olujimi A Ajijola, Estevão Scudese, Tyne W Miller Fleming, André Kinder, Chandravanu Dash, Anita M Quintana, Bret C Mobley, Julia D Berry, Pooja Jadiya, Dao-Fu Dai, Annet Kirabo, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Renata Oliveira Pereira, Debra D Murray, Joyonna Gamble-George, Melanie R McReynolds, Antentor Hinton.

  Due to aging, the efficiency of kidney function begins to decrease. Dysfunction in mitochondria and their cristae is a hallmark of aging. Therefore, age-related decline in kidney function could be attributed to changes in mitochondrial ultrastructure, increased reactive oxygen species, and alterations in metabolism and lipid composition. We sought to understand how mitochondrial ultrastructure is altered over time in tubular kidney cells. A serial block face-scanning electron microscope and manual segmentation using the Amira software were employed to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we demonstrate that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney during aging. Disruption of the MICOS complex resulted in altered mitochondrial metabolic function and increased ROS levels. We found significant, detrimental structural changes in the mitochondria of aged kidney tubules, suggesting a potential mechanism underlying the increased frequency of kidney disease with aging. We hypothesize that disruption of the MICOS complex exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, which impacts kidney health.

Keywords:  3DEM; MICOS complex; kidney; metabolism; mitochondria

DOI:  https://doi.org/10.1111/acel.70534
Front Cell Dev Biol. 2026 ;14 1809292

Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.

Jili Wang, Xiaoyu Li, Xiaoge Wang, Linyi Wang, Yandong Zhang, Xiaokun Dong, Xiangpeng Lu, Shangzeng Wang.

  Osteoporosis (OP) is primarily characterized by reduced bone mass, microarchitectural deterioration, and an increased susceptibility to fragility fractures. A central pathological feature of OP is the progressive impairment of osteogenic differentiation and bone matrix production in osteoblasts. The endoplasmic reticulum (ER), a pivotal organelle responsible for secretory protein folding, lipid/sterol biosynthesis, and intracellular Ca2+ storage, is subjected to a substantial secretory burden during osteogenic differentiation and functions as a critical regulatory hub integrating metabolic stress, inflammatory signaling, and mineralization-associated calcium signaling. Emerging evidence indicates that disruption of ER homeostasis regulates osteogenic differentiation through the three canonical branches of the unfolded protein response (UPR), including PERK-eIF2α-ATF4, IRE1α-XBP1, and ATF6 signaling pathways. In parallel, selective ER autophagy (ER-phagy) dynamically regulates ER quality control during osteogenic differentiation through removal of damaged ER domains and misfolded substrates such as procollagen. In addition, ER Ca2+ stores and STIM/ORAI-mediated store-operated Ca2+ entry (SOCE) cooperatively maintain calcium homeostasis during osteogenesis and regulate spatiotemporal expression of osteogenic transcription factors, including Runx2 and Sp7, through Ca2+ oscillatory signaling. ER membrane lipid composition further modulate osteogenic fate by influencing membrane contact site dynamics and cellular metabolic adaptation. In this review, we systematically summarize the crosstalk among ER stress, ER-phagy, Ca2+ homeostasis, and lipid metabolism during osteogenic differentiation from the perspective of ER structure-function coupling. We further discuss potential therapeutic strategies targeting ER stress regulation, including chemical chaperones and UPR/autophagy modulators, to provide new insights for targeted therapeutic approaches for osteoporosis.

Keywords:  ER-phagy; calcium homeostasis; endoplasmic reticulum stress; lipid metabolism; osteogenic differentiation

DOI:  https://doi.org/10.3389/fcell.2026.1809292
J Clin Pharmacol. 2026 May;66(5): e70209

170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.

Volkmar Weissig.

  One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.

Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.1002/jcph.70209
Narra J. 2026 Apr;6(1): e3042

Oxidative stress as a converging mechanism of aging and neurodegeneration: From molecular pathways to therapeutic targets.

Meutia A Faradilla, Karina S Anastasya, Deasyka Yastani, Yohana Yohana, Endrico X Tungka, Suweino Suweino.

  Aging is the primary risk factor for major neurodegenerative disorders, yet the precise molecular links between biological aging and progressive neuronal loss remain complex. Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, has emerged as a central converging mechanism driving both processes. This review aims to synthesize current evidence demonstrating how chronic redox imbalance drives cellular senescence and neuronal vulnerability through mitochondrial dysfunction, lipid peroxidation, and oxidative protein damage. These insights underscore how sustained oxidative insults promote the misfolding and aggregation of disease-defining proteins, including amyloid-beta in Alzheimer's disease and α-synuclein in Parkinson's disease, thereby amplifying neuroinflammation, synaptic dysfunction, and bioenergetic failure. Furthermore, antioxidant-based therapeutic strategies are critically reassessed, highlighting a paradigm shift from non-specific radical scavenging toward targeted modulation of endogenous defense systems, particularly NRF2 signaling and mitochondria-directed antioxidants. By integrating molecular mechanisms with translational perspectives, this review integrates molecular, cellular, and translational evidence to explain how oxidative stress links biological aging to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases.

Keywords:  Oxidative stress; aging; mitochondria; neurodegeneration; reactive oxygen species

DOI:  https://doi.org/10.52225/narra.v6i1.3042
Pathol Res Pract. 2026 May 09. pii: S0344-0338(26)00164-0. [Epub ahead of print]284 156511

The complex mechanistic network of periprosthetic osteolysis: Integration from inflammatory response and tissue stress to signaling pathways.

Yang Bai, Longlong Wang, Yuan Li, XiaoLong Li, Lei Wang.

  Periprosthetic osteolysis (PPO) is the main pathophysiological mechanism responsible for aseptic loosening of a prosthesis following a total joint arthroplasty, adversely affecting long-term prosthetic fixation and clinical outcomes. The pathogenesis is primarily rooted in a cascade of biological responses induced by wear particles produced at the prosthesis-bone interface. These particles are identified by pattern recognition receptors (PRRs) on the surface of macrophages, which trigger the activation of signal transduction pathways, including the TLR/NF-κB pathway and the NLRP3 inflammasome. These events lead to the release of multiple pro-inflammatory cytokines, thereby initiating a chronic local inflammatory process, which then modulates the RANKL/RANK/OPG axis, resulting in the loss of the dynamic homeostatic balance of bone metabolism. Recent evidence has shown that PPO is a complicated pathophysiological process that encompasses multiple contributing factors. In addition to wear particles, other tissue stressors (e.g., mechanical stress, hypoxia, oxidative stress) associated with the prosthesis act in concert to alter cellular fates in mesenchymal stromal cells (MSCs), bone marrow-derived macrophages (BMMs), and osteoblasts, which include cellular senescence, apoptosis, pyroptosis, and autophagy, leading to significant amplification of inflammatory and bone resorption-associated processes. Furthermore, these inflammatory processes initiate several signaling pathways that together establish a complicated regulatory network that works together to coordinate the progression of PPO. Among these signals, the RANKL/RANK/OPG axis acts as a central regulatory node by activating adaptive MAPK and NF-κB signaling pathways to coordinate local inflammatory responses and osteoclast differentiation, in addition to blocking osteoblast differentiation via Wnt/β-catenin signaling pathways, resulting in the loss of bone to create a pathological state of increased resorption and decreased formation of bone. Therefore, this review is designed to integrate new findings and to form a composite mechanistic framework that describes the immuno-inflammatory response, tissue stress, altered cell fate, and staged signaling pathways. It systematically breaks down the interaction among these factors and how they culminate in a loss of bone homeostasis, which informs our understanding of how PPO progresses. Thereby, this research enhances our ability to increase the longevity of artificial joints in order to improve the post-operative quality of life for patients.

Keywords:  Bone Homeostasis; Inflammatory Response; Periprosthetic Osteolysis; Signaling Pathways; Wear Particles

DOI:  https://doi.org/10.1016/j.prp.2026.156511