bims-mihora 2026-02-08 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–02–08
eleven papers selected by
Lisa Patel, Istesso

Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.
Leveraging mitochondrial stress to improve healthy aging.
Dying oligodendrocytes persist without mitochondria.
Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR.
USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy.
Mitochondrial superoxide signals shield the nucleus to delay ageing.
LncRNA-Gm5532 deficiency alleviates bone resorption by inhibiting mitochondrial respiration through iASPP/NRF2.
Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.
Mapping Leak Electron Pathways from Mitochondria to the Outer Cell Membrane in Human Embryonic Lung Fibroblasts.

Curr Opin Neurol. 2026 Jan 30.

Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.

Fanny Eysert, Gaëlle Deportes, Elodie Delaquaize, Mounia Chami.

   PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD.
RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients.
SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.

Keywords:  Alzheimer's disease; biomarkers; mitochondria; mitophagy; peripheral cells and fluids

DOI:  https://doi.org/10.1097/WCO.0000000000001457
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2526598123

Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.

Yixin Liu, Jagannath Misra, Debarshi Ryan Bhowmik, Brady O'Boyle, Kirk A Staschke, Natarajan Kannan, Ronald C Wek, Natalia Jura.

  The general control nonderepressible 2 (GCN2) is a conserved stress-responsive protein that plays a critical role in restoring cellular homeostasis in the integrated stress response (ISR). In response to amino acid starvation or ribosome stalling and collisions, GCN2 phosphorylates the translation initiation factor eIF2α, conferring translational control to alleviate stress. GCN2 is a multidomain protein, containing a tandem kinase domain (KD) and a catalytically inactive pseudokinase domain (ψKD). Stress-induced activation of the kinase domain requires allosteric regulation and dimerization mediated by its regulatory domains. While the pseudokinase domain is essential for GCN2 function in yeast, its mechanistic role remains unclear and underexplored in other organisms. Here, we present the first crystal structure of the human GCN2 ψKD, revealing its distinct structural features. The structure visualizes an insertion N-terminal to helix αC unique to the GCN2 ψKD that interacts with the pseudoactivation loop, stabilizing an inactive conformation. Further structural analysis shows that the ψKD forms a dimer in the crystal lattice via a network of hydrophobic and electrostatic interactions spanning both the N- and C-lobes. Mutations that disrupt the dimer interface reduced downstream ATF4 expression that is important for stress adaptation, underscoring the functional significance of the GCN2 ψKD dimer in regulating GCN2 activity. Complementary AI-guided structure predictions indicate that the dimeric GCN2 ψKD architecture is conserved across evolution. These results support the role of ψKD dimerization as a regulatory feature in GCN2-mediated ISR signaling.

Keywords:  ATF4 translation; GCN2; dimerization; integrated stress response; pseudokinase

DOI:  https://doi.org/10.1073/pnas.2526598123
Sports Med Health Sci. 2026 Jan;8(1): 23-33

Leveraging mitochondrial stress to improve healthy aging.

Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.

  Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.

Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training

DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
bioRxiv. 2026 Jan 22. pii: 2026.01.19.699752. [Epub ahead of print]

Dying oligodendrocytes persist without mitochondria.

Xhoela Bame, S Zoela Gilani, Yasmine Kamen, Robert A Hill.

Myelin is an insulating, multi-layered membrane that supports axonal integrity and neural communication. Different stressors impair myelinating oligodendrocytes, leading to demyelination, inflammation, and neurodegeneration. The intracellular processes underlying oligodendrocyte degeneration and death are unclear. Here, using optically targeted DNA damage that causes single-cell demyelination, we reveal that injured mature oligodendrocytes lose mitochondria within days and persist without them for weeks to months before cell death. This differs from other oligodendrocyte lineage cells, which exhibit acute mitochondrial changes followed by rapid cell death. Conditional deletion of the mitochondrial-related gene, Fis1 , in mature oligodendrocytes, similarly causes acute loss of mitochondria and prolonged cell death. The unique cell death is characterized by nuclear changes, intracellular stress, and markers of disease-associated oligodendrocytes. Thus, mitochondrial loss may be an early marker of oligodendrocyte pathology, and mitochondrial quality control is required for oligodendrocyte and myelin homeostasis.

DOI: https://doi.org/10.64898/2026.01.19.699752
bioRxiv. 2026 Jan 23. pii: 2026.01.22.701145. [Epub ahead of print]

Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.

Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.

As highly dynamic organelles, mitochondria play an essential role in neuronal survival and synaptic function. Excitotoxicity is as a critical factor that promotes mitochondrial dysfunction after traumatic brain injury (TBI). Intercellular mitochondrial transfer and exogenous mitochondrial transplantation are emerging concepts to understand mitochondrial trafficking in response to mitochondrial dysfunction; however, robust in vivo evidence remains limited on the extent of these processes in the central nervous system (CNS). There is a significant knowledge gap in our understanding of mitochondrial transfer mechanisms under both normal physiological conditions and after experimental TBI. Mouse lines expressing mitochondrial green-fluorescent dendra-2 (mtD2) and GFP (mtGFP) targeted to inner and outer mitochondrial membranes, respectively, were used to study astrocyte-specific (Aldh1l1-CreER; mtD2 f/f - AmtD2 and Aldh1l1-CreER; mtGFP f/f - AmtGFP) and neuron-specific (CamK2aCre; mtD2 f/f - NmtD2 and CamK2aCre; mtGFP f/f - NmtGFP) mitochondrial dynamics and bioenergetics in acute TBI and excitotoxicity. At 24 hrs following TBI, neurons in the NmtD2 mouse brain exhibited rapid and significant alterations in mitochondrial morphology, including changes in total mitochondrial volume, volume distribution, and sphericity. Synaptic neuronal (SN) mitochondria display robust deficits in mitochondrial bioenergetics and complex protein levels while non-synaptic neuronal (NSN) mitochondria show State III bioenergetics and complex proteins at control levels. These findings are accompanied by a marked increase in astrocyte-derived mitochondria (AmtGFP) transfer to neurons at 24 hrs post-injury, compared to control animals, but no increase in transfer to neuronal synapses. While TBI also altered astrocytic mitochondrial morphology in the cortex, astrocytic mitochondrial bioenergetics remained preserved. Single-cell RNA-seq analysis of astrocytes revealed significant transcriptional reprogramming following TBI, characterized by the upregulation of genes associated with mitochondrial homeostasis and the machinery for organelle trafficking. In vitro co-cultures of primary cortical astrocytes and neurons demonstrated that astrocytes can transfer mitochondria to neurons via direct contact and that NMDA-mediated excitotoxicity further enhanced this astrocyte-to-neuron mitochondrial transfer. Furthermore, astrocytic-derived extracellular vesicles containing mitochondria (EV-mito) deliver mitochondria to neurons and EV-mediated mitochondrial transfer significantly ameliorated NMDA-induced mitochondrial dysfunction in primary cortical neurons. Together, these findings show that astrocytes take on a TBI-related phenotype that facilitates dynamic changes in mitochondrial networks and mitochondrial trafficking to neurons. Astrocytic transfer of respiratory-competent mitochondria support is an intrinsic neuroprotective response to injury that supports mitochondrial function in neuronal soma, dendrites, and axons but not at the neuronal synapse. Finally, we show therapeutic potential of exogenous mitochondrial transfer, particularly via EV-mito, for treating neurological disorders associated with excitotoxicity, such as TBI.

DOI: https://doi.org/10.64898/2026.01.22.701145
ACS Chem Neurosci. 2026 Feb 05.

CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR.

Dongni Wen, Yunjing Li, Lina Chen, Haoling Xu, Yingqing Wang, Yanhong Weng, Jing Zhang, Xiaochun Chen, En Huang, Yuqi Zeng, Qinyong Ye.

  Parkinson's disease (PD) is characterized by mitochondrial dysfunction and impaired protein homeostasis, with the mitochondrial unfolded protein response (mtUPR) emerging as a key regulatory pathway in mitigating mitochondrial stress. This study aimed to explore the impact of shRNAs targeting CHCHD2 or FBXO7 on the mitochondrial unfolded protein response (mtUPR) in a Parkinson's disease (PD) cell model, clarify the mitochondrial-nuclear signaling pathways involving CHCHD2 and FBXO7, elucidate the mechanisms underlying mitochondrial dysfunction induced by these genes, and identify new therapeutic targets for early stage PD. An in vitro PD model was established by treating SH-SY5Y cells with MPP+; mitochondrial morphology was evaluated using transmission electron microscopy, and qRT-PCR and Western blot were employed to determine the expression levels of mRNAs and proteins associated with mtUPR, autophagy, CHCHD2, and FBXO7 under oxidative stress. In the MPP+-induced PD cell model, we knocked down CHCHD2 and FBXO7 via shRNA and treated the cells with JNK and AKT agonists to observe their effects on mtUPR protein expression. The results showed that mtUPR was activated in MPP+-exposed SH-SY5Y cells, and the expression of CHCHD2 and FBXO7 genes was significantly upregulated after MPP+ intervention; knockdown of CHCHD2 via shRNA resulted in a marked decrease in the expression of mtUPR-related proteins such as HSPA9, HSPD1, YME1L1, and CLPP, while shRNA targeting FBXO7 exerted only a minimal effect on these mtUPR proteins. Furthermore, the administration of JNK or AKT agonists significantly enhanced the expression of MPP+-induced mtUPR proteins, including HSPA9, HSPD1, YME1L1, and CLPP. Collectively, these findings indicate that CHCHD2, rather than FBXO7, plays an essential role in modulating the MPP+-induced mtUPR and suggest that CHCHD2 may regulate mitochondrial protein homeostasis by activating the mtUPR through the JNK/c-Jun and AKT/ERα pathways.

Keywords:  CHCHD2; FBXO7; Parkinson’s disease; mtUPR

DOI:  https://doi.org/10.1021/acschemneuro.5c00792
JBMR Plus. 2026 Mar;10(3): ziag004

USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy.

Shuang Jiang, Danling Chen, Rui Sheng, Quan Yuan, Jian Pan, Yuchen Guo.

  The pain and dysfunction caused by temporomandibular joint osteoarthritis (TMJ OA) can be debilitating. However, effective disease-modifying medicine for TMJ OA remains an unfulfilled need. While progressive cartilage degradation represents the hallmark of TMJ OA, the underlying molecular mechanisms remain incompletely understood. Here, we identify ubiquitin-specific protease 34 (USP34) as a key regulator of mitochondrial quality control in TMJ chondrocytes through its stabilization of adenine nucleotide translocase 1 (ANT1). Using chondrocyte-specific Usp34 KO (Usp34icKO ) mice, we first demonstrated age-dependent TMJ OA development characterized by cartilage destruction. Subsequent unilateral bite-raising experiments revealed that USP34 deficiency exacerbated mechanical stress-induced TMJ degeneration. Our results disclosed the dual protective role of USP34 against both age-related and mechanical stress-related TMJ degeneration. Mechanistically, we define the USP34-ANT1 axis as a component upstream of the PINK1-Parkin pathway. USP34 deubiquitinates and stabilizes ANT1, thereby promoting the initiation of Parkin-dependent mitophagy. Additionally, USP34 overexpression confers protection to chondrocytes against cellular injury. These findings establish USP34 as a critical node linking ubiquitin signaling to mitochondrial homeostasis in TMJ chondrocytes and propose targeting USP34 or ANT1 as a potential disease-modifying strategy.

Keywords:  cell signaling; chondrocytes; deubiquitinating enzymes; osteoarthritis; temporomandibular joint disorders

DOI:  https://doi.org/10.1093/jbmrpl/ziag004
Nat Metab. 2026 Feb 03.

Mitochondrial superoxide signals shield the nucleus to delay ageing.

DOI: https://doi.org/10.1038/s42255-026-01461-8
Cell Biol Toxicol. 2026 Feb 04.

LncRNA-Gm5532 deficiency alleviates bone resorption by inhibiting mitochondrial respiration through iASPP/NRF2.

Jian Zhang, Xingtao Zhang, Lingyan Zhang, Gang Yao, Hai Zhao, Penghai Qiao, Tao Xue.

  Osteoporosis, characterized by excessive osteoclast activity and bone resorption, is closely linked to mitochondrial respiration. The long non-coding RNA Gm5532 (Gm5532) has been implicated in osteoclast differentiation, but its role in mitochondrial function remains unclear. This study aimed to elucidate the mechanism by which Gm5532 regulates bone resorption through iron metabolism and mitochondrial respiration, focusing on its interaction with iASPP and the NRF2 signaling pathway. Here, we show that Gm5532 KO alleviates bone loss in aged, ovariectomized, and iron-overloaded mice by reducing osteoclast formation and activity. Mechanistically, Gm5532 directly interacts with the RNA-binding protein iASPP. This interaction modulates the KEAP1/NRF2 axis, leading to the destabilization of NRF2. Gm5532 KO enhances iASPP-KEAP1 binding, thereby stabilizing NRF2 and upregulating its target genes: Ftl, Fth, and Fpn1. This cascade reduces the intracellular labile iron pool. Iron deficiency suppresses mitochondrial biogenesis and respiration, and ultimately, inhibites osteoclast differentiation. In summary, Gm5532 functions as a critical regulator of bone resorption through its modulation of iron homeostasis and mitochondrial respiration. Our study uncovers a novel Gm5532-iASPP-NRF2 signaling axis that links iron metabolism to mitochondrial respiration and osteoclast function, offering a promising potential therapeutic target for osteoporosis.

Keywords:  Iron metabolism; LncRNA-Gm5532; Mitochondrial respiratory; NRF2; Osteoclast; iASPP

DOI:  https://doi.org/10.1007/s10565-026-10158-3
Cell Rep Med. 2026 Feb 03. pii: S2666-3791(26)00002-9. [Epub ahead of print] 102585

Acutely denervated muscle EVs reshape neuronal mitochondrial metabolism via retrograde signaling to rescue peripheral nerve injury.

Qi Liu, Borui Xue, Yongfeng Zhang, Mingze Qin, Ziqing Zhu, Zhenguo Wang, Hongyu Li, Shuanshuan Fan, Meijia Su, Shengyou Li, Shijie Yang, Anhui Qin, Teng Ma, Xue Gao, Huiling Sun, Yiming Hao, Lingli Guo, Shihao Nie, Jiaqi Wang, Zhuojing Luo, Jinghui Huang, Bing Xia.

  Peripheral nerve injury causes muscle atrophy due to slow axonal regeneration, highlighting an unmet therapeutic need. Although neuromuscular interactions are classically viewed as unidirectionally nerve dominated, we show that acutely denervated muscle (adMu) regulates nerve regeneration via a retrograde signaling pathway. adMu initiates a trans-tissue regulatory mechanism through extracellular vesicles (EVsadMu) that orchestrate neural energy homeostasis to accelerate regeneration. Functional profiling identifies IDH2 and CS as key metabolic enzymes within EVsadMu. Neurons treated with EVsadMu exhibit a 1.39-fold increase in NADPH/NADP+ ratio via IDH2, along with a 1.18- and 1.27-fold increase in NADH/NAD+ and FADH2/FAD ratios via CS, fueling the tricarboxylic acid (TCA) cycle to enhance mitochondrial bioenergetics. This restores redox balance and energy supply, driving axonal regeneration. In sciatic nerve injury models, EVadMu-microneedle conduits significantly promote energy metabolism and functional recovery. Together, our findings position adMu as a metabolic signaling center enabling retrograde regulation for nerve regeneration, offering potential for clinical translation.

Keywords:  acute denervation; extracellular vesicles; mitochondrial metabolism; muscle; peripheral nerve injury

DOI:  https://doi.org/10.1016/j.xcrm.2026.102585
Bioelectricity. 2025 Sep;7(3): 180-191

Mapping Leak Electron Pathways from Mitochondria to the Outer Cell Membrane in Human Embryonic Lung Fibroblasts.

Guanzhen Gao, Huiqin Wang, Yanan Ding, Jingke Guo, Jianwu Zhou, Lijing Ke, Pingfan Rao, Suyun Zhang, Tianbao Chen, Chris Shaw, Huaiyu Gu.

   Background: It is widely accepted that the inevitable leakage of electrons from mitochondria during respiratory metabolism is managed intracellularly through a complex cascade involving the conversion and transport of reactive oxygen species (ROS) and antioxidant mechanisms. However, considering that electrons can travel through various media, including biomacromolecules, do leaked electrons from the electron transport chain necessarily undergo complicated intracellular disposal processes? Here, we demonstrate that leaked electrons may actually be transported out of the cell.
Methods: By expressing circularly permuted yellow fluorescent protein (cpYFP), a superoxide indicator, at the microtubules, actin, and integrin of human embryonic lung fibroblasts.
Results: All three corresponding transgenic strains emitted fluorescent light, illuminating an ROS pathway from mitochondria to the outer cell membrane. The fluorescent intensity was positively correlated with mitochondrial superoxide content and aerobic respiratory intensity but was independent of cytosolic ROS levels.
Conclusion: These results suggest that leaked electrons are transported out of the cell in their electron form. We anticipate that our findings will serve as a starting point for revising the understanding of ROS generation and homeostasis, implicating various physiological and pathological processes.

Keywords:  ROS pathway; cell membrane; leaked electrons; mitochondria

DOI:  https://doi.org/10.1177/25763113251366197