bims-miptne 2026-08-16 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–08–16
fourteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Orai1-mediated Ca2+ entry regulates lipolysis and mitochondrial activation in brown adipose thermogenesis.
Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.
The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants.
Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy.
The calcium-binding protein CSE links Ca2+ signaling with cell-cell communication in cyanobacteria.
Distinct types of dendritic Ca2+ spikes in CA3 pyramidal neurons associated with neuronal activity changes during navigation.
Mitochondrial calcium uniporter as a biomarker in lung adenocarcinoma: regulation of the immune microenvironment, apoptosis, cell cycle and mitophagy.
Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.
A cryptic allosteric pocket shapes isoform-selective inhibition of human malic enzymes.
Mitochondria Dictate Progressive Versus Bimodal Aging of the Mammary Gland.
Umbilical cord-derived mitochondrial transplantation restores tendon structure and function in a preclinical model of achilles tendinopathy.
Metformin Attenuates Sepsis-Induced Cardiomyopathy via Inhibition of Reverse Electron Transfer at Mitochondrial Complex I.

Exp Mol Med. 2026 Aug 13.

Orai1-mediated Ca2+ entry regulates lipolysis and mitochondrial activation in brown adipose thermogenesis.

Suji Kim, Phan Anh Nguyen, Kyu-Sang Park, Seung-Kuy Cha, Jun Namkung.

Cold-induced thermogenesis in brown adipose tissue is essential for maintaining energy homeostasis, yet the Ca2+-dependent mechanisms underlying this process remain incompletely understood. Here, we identify Orai1, a component of the store-operated Ca2+ entry pathway, as a regulator of thermogenic activation in brown adipose tissue. Using a brown adipocyte-specific Orai1 knockout mouse model, we demonstrate that cold exposure is associated with Orai1-dependent Ca2+ influx through a non-canonical mechanism. Orai1 deficiency impairs cAMP-protein kinase A signalling, reduces the expression of lipolytic enzymes and thermogenic genes, and diminishes mitochondrial Ca2+ uptake and uncoupling. These defects culminate in cold intolerance, lipid accumulation and decreased energy expenditure. Mechanistically, Orai1 facilitates Ca2+-dependent activation of adenylyl cyclase 3, linking membrane Ca2+ entry to cAMP production, and promotes mitochondrial remodelling and oxidative metabolism. These findings support a key role for Orai1 in coordinating Ca2+ entry to lipolytic and mitochondrial pathways in brown adipocytes and highlight Orai1 as a potential therapeutic target in metabolic diseases characterized by impaired energy metabolism.

DOI: https://doi.org/10.1038/s12276-026-01808-x
iScience. 2026 Aug 21. 29(8): 117071

Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.

Makoto Sano, Hideaki Ijichi, Sho Tabata, Akiyoshi Hirayama, Shuichi Shimma, Yohei Masugi, Yoshimi Ichimaru, Jinsuk Kim, Gen Kimura, Koji Miyabayashi, Ryota Takahashi, Hiroto Hatakeyama, Takahiro Suzuki, Atsushi Masamune, Tomoyoshi Soga, Mitsuhiro Fujishiro.

  Pancreatic ductal adenocarcinoma (PDAC) is the cancer with poorest prognosis, with metabolic reprogramming reported. We investigated metabolic alterations in mice with PDAC using capillary electrophoresis-mass spectrometry (CE-MS) and mass spectrometry imaging (MSI). o-Acetylcarnitine, a metabolite of carnitine, and acetyl-CoA increased during cancer progression in a PDAC mouse model by CE-MS, while MSI revealed that o-acetylcarnitine was mainly localized in PDAC cells. Also, immunohistochemistry showed overexpression of γ-butyrobetaine 2-oxoglutarate dioxygenase 1 (BBOX1), which synthesizes carnitine from γ-butyrobetaine, mainly in PDAC cells. Meldonium, an inhibitor of BBOX1, inhibited PDAC proliferation and cytokine secretion, thereby prolonging the survival of PDAC-bearing mice, accompanied by improved skeletal muscle atrophy. In patients undergoing PDAC resection, BBOX1 expression was determined as an independent poor prognostic factor for overall survival. Therefore, these results suggest that blocking L-carnitine synthesis would improve the prognosis of patients with PDAC.

Keywords:  BBOX1; CE-MS; MSI; PDAC; cachexia; capillary electrophoresis-mass spectrometry; mass spectrometry imaging; meldonium; metabolome; o-acetylcarnitine; overall survival; pancreatic cancer; pancreatic ductal adenocarcinoma; γ-butyrobetaine 2-oxoglutarate dioxygenase 1

DOI:  https://doi.org/10.1016/j.isci.2026.117071
Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):

The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.

Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.

  Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.

Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy

DOI:  https://doi.org/10.3390/cells15151371
Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2607733123

Ca2+ regulation of PMCA2 calcium pump expression in hair cells of Tmc1 deafness mutants.

Amanda Bryn Rolseth, Maryline Beurg, Dakota Elle Konrad, Benjamin K August, Robert Fettiplace.

  Mutations in transmembrane channel-like protein 1 (TMC1), the pore-forming component of the mechano-electrical transducer (MET) channel in auditory hair cells, cause cell death and deafness in 3-wk old mice. We studied mice with mutations Tmc1 p.T416K, p.M412K, p.D528N, and p.D569N, which possessed functional MET channels at postnatal day (P)6 but became deaf before P21. These Tmc1 mutants had channels with reduced Ca2+ permeability and lower expression of the PMCA2 calcium pump in outer hair cell (OHC) stereocilia. The reduction in PMCA2 density was directly correlated with reduced Ca2+ entry via the MET channel. Over the first postnatal week, PMCA2 expression decreased in cochlear cultures containing lowered extracellular Ca2+, but after P11, PMCA2 density was insensitive to Ca2+ changes. The lower PMCA2 density in mutants was maintained into adulthood and may contribute to hair cell death. Before the onset of hearing, PMCA2 continuously turns over, and its insertion into stereocilia from an identified vesicular compartment is regulated by cytoplasmic [Ca2+]. PMCA2 turnover was strongly inhibited by the endocytosis blocker, Pitstop2, and by PtdIns(4,5)P2 blockers like phenylarsine oxide (PAO), which was shown to elevate stereociliary [Ca2+]. We argue the effects of PAO on mechanotransduction may be partly due to this Ca2+ increase. OHC bundles also expressed Neuroplastin (NPTN), a PMCA2 accessory protein, whose development paralleled PMCA2, and we propose it stabilizes the pump complex in stereocilia. NPTN expression was delayed about 2 d relative to PMCA2 and was less Ca2+ sensitive, implying it originates from a different internal pool of vesicles.

Keywords:  PMCA calcium pump; TMC1; deafness; hair cell; neuroplastin

DOI:  https://doi.org/10.1073/pnas.2607733123
Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00935-6. [Epub ahead of print]45(8): 117857

Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.

Koyeli Das, Rituparna Samanta, Tamar Ziv, Johannes M Herrmann, Bella Kalderon, Ophry Pines.

  Tim23 is an essential component of the mitochondrial inner membrane translocase and Sfc1 is a carrier that exchanges succinate for fumarate across that membrane. Sfc1 and succinic acid availability regulate dual targeting of fumarase and aconitase by facilitating mitochondrial import of their newly synthesized precursors, as shown by pulse-chase experiments. Here, we show that Sfc1 associates with Tim23 in vivo, and succinate modulates this association, which in turn affects mitochondrial protein import. Physical interaction between Tim23 and Sfc1 was proven by co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) and biotin-based proximity labeling (TurboID). Proximity labeling and structural modeling-informed mutagenesis allowed us to dissect the carrier activity of Sfc1 from its function as a TIM23 regulator. We performed Rosetta-MP docking of Sfc1 and Tim23 to envisage the interface. Thus, our findings show that metabolites can regulate mitochondrial import and adjust the segregation of key metabolic enzymes between the cytosol and mitochondria.

Keywords:  CP: cell biology; CP: metabolism; Tim23; aconitase; dual targeting; fumarase; glyoxylate shunt; metabolic signaling; metabolites; mitochondrial protein import; succinate-fumarate carrier; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.celrep.2026.117857
Nat Nanotechnol. 2026 Aug 10.

Oral nano-delivery of a gut microbial metabolite enhances T cell stemness for cancer immunotherapy.

Kai Han, Young Seok Cho, Mariko Takahashi, Xingwu Zhou, Hannah E Dobson, Kim Hutchings, Yuesong Wu, Youngseo Na, Fang Xie, Julia Crowther, Jinmei Wu, Jin Xu, Chuan Lee, Himani Jasewicz, Yujin Kim, Minal Nenwani, Olamide Animasahun, Fulei Wuchu, Anthony Andren, Harrison Wong, Emma Camp, Ziye Wan, Qi Wu, Li Zhang, Cheng Xu, Katherine Dong, Yao Xu, Anna Schwendeman, Grace Y Chen, Yuying Xie, Costas A Lyssiotis, Martin Clasby, Deepak Nagrath, Yu Leo Lei, James J Moon.

Gut microbial metabolites play crucial roles in regulating systemic immunity, but their mechanisms and limited drug-like properties remain unresolved. Here we report an oral nano-formulation that leverages gut microbial metabolites to modulate T cell metabolism and amplify antitumour immunity. Through an in vitro screening of gut microbial metabolites, we identified 3,4-dihydroxybenzoic acid that improved adoptive T cell therapy and enhanced CD8+ T cell stemness by suppressing glycolysis and regulating the Akt-mTORC1-Myc pathway. To harness the potency of 3,4-dihydroxybenzoic acid for systemic cancer immunotherapy, we engineered a 3,4-dihydroxybenzoic acid prodrug nano-emulsion, significantly increasing its oral absorption and half-life. In multiple murine tumour models, the oral nano-emulsion enhanced the expansion of antigen-specific, stem-like CD8+ T cells, sensitizing tumours to anti-PD-1 blockade and exerting robust antitumour efficacy. By integrating nanotechnology with microbial-metabolite-based immunotherapy, this study establishes a mechanistic link between the gut microbiota and T cell immunity, offering a promising approach for cancer immunotherapy.

DOI: https://doi.org/10.1038/s41565-026-02235-9
EMBO J. 2026 Aug 13.

The calcium-binding protein CSE links Ca2+ signaling with cell-cell communication in cyanobacteria.

Teresa A Müller, Felicia Stahlecker, Karolina Roganowicz, Sherihan Samir, Gregor L Weiss, Murray Coles, Khaled A Selim.

Multicellular cyanobacteria have evolved sophisticated cell-cell communication machinery to exchange, synchronize, and coordinate the efforts of individual cells. Analogous to gap junctions that have traditionally been regarded as a eukaryotic feature, multicellular cyanobacteria coordinate their cell-cell communication via septal junctions (SJs). However, the signals that regulate cell-cell communication and septal-junction assembly are largely unknown. Lately, calcium signaling has been implicated in regulating cell junctions in eukaryotes. We recently discovered a Ca2+-binding protein, CSE, which is exclusively found in multicellular cyanobacteria. Here, we investigate CSE as a potential link between calcium signaling and cell-cell communication. We solve the NMR structure of CSE in its Ca2+-bound state and revealed that CSE acts as Ca2+-buffer protein. Using cryo-electron tomography, we find that Δcse mutant cells display significantly fewer septal junctions as well as SJ precursors known as nanopores. This indicates that CSE is not only essential for Ca2+ homeostasis, but also mediates cell-cell communication via regulating SJs and nanopores formation, and establishes Ca2+ signaling and CSE as key players regulating cyanobacterial multicellularity. Furthermore, these findings highlight calcium signaling as a conserved principle for regulating cellular junctions in organisms that diverged a billion years ago.

DOI: https://doi.org/10.1038/s44318-026-00893-y
Sci Adv. 2026 Aug 14. 12(33): eaec6015

Distinct types of dendritic Ca2+ spikes in CA3 pyramidal neurons associated with neuronal activity changes during navigation.

Snezana Raus Balind, Balázs Lükő, Imola Plangár, Martin Blazsek, Balázs B Ujfalussy, Judit K Makara.

Active dendrites enrich single-neuron computations by performing nonlinear input integration, including generation of dendritic spikes. Diverse dendritic spike types have been found in various cortical neuron classes in vitro; however, their in vivo prevalence and roles remained elusive. We measured calcium activity in apical dendrites and soma of pyramidal cells in the hippocampal area CA3 (CA3PCs) during virtual navigation in mice. Although dendritic activity was generally synchronous with the soma, their correlation decreased with dendritic distance. We identified two types of regenerative dendritic activities: slow, large-amplitude global Ca2+ events representing putative Ca2+ plateaus and fast Ca2+ events with large dendrite-to-soma attenuation, representing putative dendritically initiated Ca2+ spikes. Ca2+ plateaus contributed to spatially tuned activity but only occasionally induced new place fields, suggesting conditional induction of synaptic plasticity. In contrast, fast Ca2+ spikes were often followed by transient increase in somatic activity without spatial tuning, suggesting increased excitatory inputs or excitability. Our results unveil previously unidentified mechanisms whereby dendritic activity shapes output of CA3PCs in vivo.

DOI: https://doi.org/10.1126/sciadv.aec6015
Am J Cancer Res. 2026 ;16(7): 2783-2800

Mitochondrial calcium uniporter as a biomarker in lung adenocarcinoma: regulation of the immune microenvironment, apoptosis, cell cycle and mitophagy.

Yihao Liu, Zexia Zhao, Hua Huang, Chenxuan Zhao, Zhixuan Duan, Min Wang, Chen Ding, Wenhao Zhao, Yanzhan Liu, Hongbing Zhang, Yongwen Li, Wenjun Meng, Yin Li, Xiaobin Shang, Jun Chen, Haoling Zhang, Honglin Zhao.

  The mitochondrial calcium uniporter (MCU) complex is essential for maintaining mitochondrial calcium homeostasis and regulating cellular metabolism, apoptosis, proliferation, and mitochondrial quality control. Although MCU has been implicated in multiple malignancies, its biological role and regulatory mechanisms in lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer (NSCLC), remain insufficiently defined. In this study, MCU expression was analyzed using pan-cancer and LUAD datasets from TCGA, GEO, UALCAN, and tissue microarray cohorts. GO, KEGG, and GSEA were performed to explore MCU-associated biological pathways, while ssGSEA, CIBERSORT, and TIDE algorithms were used to evaluate immune infiltration and predicted immunotherapy response. In vitro assays, including CCK-8, EdU, colony formation, Transwell assays, flow cytometry, qRT-PCR, Western blotting, immunofluorescence staining, JC-1 staining, and reactive oxygen species (ROS) detection, were conducted to assess the effects of MCU on LUAD cell behavior, mitophagy, and mitochondrial function. MCU was significantly upregulated in LUAD tissues and cell lines compared with normal controls. High MCU expression was associated with reduced immune cell infiltration, decreased immune checkpoint and HLA gene expression, and lower predicted sensitivity to immunotherapy. Functionally, MCU knockdown markedly inhibited LUAD cell proliferation, migration, and invasion, promoted apoptosis, and induced G1-phase cell cycle arrest, accompanied by increased p21 and cleaved caspase-3 expression and decreased CDK4 and Cyclin D1 expression. Conversely, MCU overexpression enhanced malignant phenotypes and suppressed apoptosis. Mechanistically, GSEA indicated that MCU was closely associated with mitophagy-related pathways. Further validation showed that MCU knockdown reduced PINK1 and PRKN expression, decreased mitochondrial LC3B accumulation, and weakened LC3B-mitochondria co-localization, indicating impaired mitophagy. MCU depletion also caused mitochondrial membrane potential dissipation and increased intracellular ROS accumulation. Collectively, these findings suggest that MCU promotes LUAD progression by remodeling the tumor immune microenvironment, enhancing malignant cellular behaviors, inhibiting apoptosis, and maintaining mitophagy-dependent mitochondrial homeostasis, highlighting MCU as a potential prognostic biomarker and therapeutic target in LUAD.

Keywords:  Mitochondrial calcium uniporter (MCU); apoptosis; cell cycle; immune microenvironment; lung adenocarcinoma (LUAD); mitophagy

DOI:  https://doi.org/10.62347/PGQK3358
Biochem Biophys Res Commun. 2026 Aug 08. pii: S0006-291X(26)01180-0. [Epub ahead of print]833 154416

Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.

Yosuke Ito, Shuangshan Dong, Hiroki Kato, Zhiyan Zhou, Lu Wang, Yuta Hirofuji, Hiroshi Sato, Pin Fee Chong, Yuichiro Hirata, Kenichiro Yamamura, Takahiro A Kato, Yasunari Sakai, Satoshi Fukumoto, Keiji Masuda.

  Type 2 ryanodine receptor (RyR2), a Ca2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2: c.9910C > G, p.Q3304E in exon 69 and c.14222C > T, p.A4741V in exon 99 (RyR269/99). RyR2-DNs showed cytosolic and mitochondrial Ca2+ accumulation, and impaired neurite outgrowth, suggesting that RyR269/99 is a gain-of-function mutation that promotes Ca2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca2+ accumulation. Thus, RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.

Keywords:  Calcium; Mitochondria; Neurodevelopment; Oxidative stress; Ryanodine receptor type 2

DOI:  https://doi.org/10.1016/j.bbrc.2026.154416
Protein Sci. 2026 Sep;35(9): e70757

A cryptic allosteric pocket shapes isoform-selective inhibition of human malic enzymes.

Ben A Krinkel, Yuliana Yosaatmadja, Mark D Slayton, Anita Krinkel, Jack Copping, Jin Heon Jeon, Joyce Eu, Kerslee Kohagen, Amir Ashoorzadeh, Jeff Smaill, Jack Flanagan, Christopher Walker, Sofia D Merajver, Kerry Loomes, Christopher J Squire.

  Malic enzymes (ME) regulate central carbon metabolism and cellular redox balance, and the mitochondrial isoform ME2 is frequently upregulated in aggressive cancers to support metabolic flexibility and stress resistance. Isoform-selective inhibition has remained out of reach because the catalytic machinery is essentially invariant across the three human enzymes (ME1-3), suggesting that selectivity must arise elsewhere than the active site. Here, we define matched kinetic and regulatory profiles for all three isoforms, highlighting key differences in substrate and cofactor dependence and metabolic regulation. Our x-ray crystal structures show that the active-site inhibitor 3',6'-dihydroxy-4,4″-dimethoxy-[1,1':4',1″-terphenyl]-2',5'-dione (NPD-389) occupies a conserved, metal-coordinating pose in all three isoforms, explaining its non-selective inhibition observed in enzyme assays. We further identify a cryptic pocket adjacent to the active site that is engaged by our probe molecule, flavianic acid (FLA), and accessible only in the mitochondrial enzymes ME2 and ME3. FLA binding locks an open, inactive enzyme conformation in place, with kinetic studies revealing isoform-specific allosteric responses and suggesting that this pocket may be a native regulatory site sensitive to the mitochondrial metabolic state. Our cellular viability assays suggest that molecules exploiting this cryptic pocket reduce proliferation in cancer cell models with elevated ME2 expression. Conformational dynamics, rather than sequence divergence at the catalytic center, can therefore generate isoform-specific regulatory and inhibitory mechanisms within a conserved enzyme family.

Keywords:  NPD‐389; allosteric regulation; cancer; flavianic acid; human malic enzyme (ME1, ME2, ME3); metabolism; structure‐based drug design; x‐ray crystallography

DOI:  https://doi.org/10.1002/pro.70757
Aging Cell. 2026 Aug;25(8): e70661

Mitochondria Dictate Progressive Versus Bimodal Aging of the Mammary Gland.

Edmund Charles Jenkins, Mrittika Chattopadhyay, Thelma Mashaka, Miguel Torres-Martin, Daniela Sia, Igor Bado, Doris Germain.

  The incidence of breast cancer shows its largest peak around the age of 65 but also a peak around 45 indicating a bimodal distribution. While some potential explanations, such as age-related enrichment in specific breast cancer sub-types and BRCA1/2 mutations were proposed, they do not explain why the peaks are at 45 and 65, raising the possibility that the way the breast ages may play a role. Here using two mouse models, we show two distinct aging patterns of the mammary gland; one being progressive, the other bimodal. In the bimodal model, waves of overlapping genes and proteins associated with breast cancer pathways are observed at 11 and 19 months but are absent at 3 and 14 months. Further, in the bimodal model, the mammary glands at 11 and 19 months are more permissive to the growth of cancer cells but not at 14 or > 22 months, while in the progressive model, the growth of cancer cells increases starting at 14 months of age. Using scRNAseq, we established a bimodal aging signature. Since 11 and 19 months in mice correlate with 45 and 65 in humans, we tested the mammary gland-derived bimodal signature in two breast cancer databases and found that the signature is enriched in women diagnosed at 45 and 65. Therefore, our study raises the possibility that distinct patterns of aging of the breast exist and that they may contribute to the bimodal distribution of breast cancer. Further, our study adds to the growing evidence of non-linear aging.

Keywords:  aging; mammary gland; mitochondria‐nuclear communication

DOI:  https://doi.org/10.1111/acel.70661
J Transl Med. 2026 Aug 07. pii: 1036. [Epub ahead of print]24(1):

Umbilical cord-derived mitochondrial transplantation restores tendon structure and function in a preclinical model of achilles tendinopathy.

Da-Yoon Kim, Mi Jin Kim, Min-Jeong Park, Mina Lim, Eun-Seo Back, Chang-Koo Yun, Seong Hun Kim, Hyuk Nam Kwon, Chaeyoung Lee, Kyunghoon Min, Yong-Soo Choi.

   BACKGROUND: Achilles tendinopathy is a degenerative musculoskeletal disorder for which disease-modifying therapies remain limited, largely due to the inability of current interventions to directly restore cellular bioenergetic function. Emerging evidence has identified mitochondrial dysfunction as a central contributor to tendon degeneration, highlighting mitochondria as a potential therapeutic target. Here, we evaluated umbilical cord-derived mitochondria (UC-MT) as a dose-defined, cell-free therapeutic strategy for tendinopathy.
METHODS: UC-MT were isolated from human umbilical cord-derived mesenchymal stem cells and characterized for mitochondrial integrity and bioenergetic activity. Therapeutic efficacy was evaluated in vitro using TNF-α-induced human tenocyte injury models and in vivo in a collagenase-induced rat model of Achilles tendinopathy. Dose-response effects were systematically assessed (5, 10, and 20 µg), and mitochondrial function, metabolic profiles, extracellular matrix remodeling, and functional recovery were analyzed using integrated molecular, histological, and functional assays, including transcriptomic and metabolomic profiling.
RESULTS: UC-MT treatment significantly restored mitochondrial membrane potential, ATP production, and respiratory complex activity in injured tenocytes, accompanied by attenuation of inflammatory signalling. Among the tested doses, 10 µg UC-MT consistently produced the most robust therapeutic effects across mitochondrial, metabolic, and structural outcome measures. In vivo, UC-MT administration improved tendon histoarchitecture, collagen organization, and functional performance, while integrated multi-omics analyses revealed coordinated metabolic reprogramming, including restoration of mitochondrial complex I-linked bioenergetic pathways.
CONCLUSIONS: Taken together, these findings position UC-MT as a dose-defined, cell-free therapeutic modality with translational potential for tendon regeneration. By directly targeting mitochondrial dysfunction, UC-MT restores mitochondrial bioenergetics and supports tendon regeneration in preclinical models of tendinopathy.

Keywords:  Achilles tendinopathy; Cell-free regenerative therapy; Mitochondrial bioenergetics; Mitochondrial transplantation; Umbilical cord-derived mitochondria

DOI:  https://doi.org/10.1186/s12967-026-08768-w
Biology (Basel). 2026 Aug 02. pii: 1267. [Epub ahead of print]15(15):

Metformin Attenuates Sepsis-Induced Cardiomyopathy via Inhibition of Reverse Electron Transfer at Mitochondrial Complex I.

Nannan He, Wen Cao, Yannian Luo, Chao Sun, Ting Zhao, Xiongxiong Liu, Meiling Li, Lin Wei, Bing Wang, Jian Liu.

  Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis; however, its molecular mechanisms remain incompletely understood, which has hindered the development of targeted therapies. We hypothesized that excessive mitochondrial reactive oxygen species (mtROS) production through reverse electron transfer (RET) at mitochondrial complex I contributes to septic myocardial injury and that metformin, a clinically used inhibitor of mitochondrial complex I, protects the myocardium by inhibiting this process. In lipopolysaccharide-stimulated H9C2 cardiomyocytes and cecal ligation and puncture-induced septic rats, sepsis was characterized by an elevated mitochondrial membrane potential, accompanied by succinate accumulation, an increased NADH/NAD+ ratio, and impaired downstream electron transport. These metabolic changes established favorable conditions for RET-mediated mtROS generation. Metformin inhibited complex I activity and selectively suppressed RET-mediated mtROS generation without increasing ROS production associated with forward electron transport (FET). This effect was accompanied by attenuated inflammatory responses and apoptosis. In septic rats, metformin preserved cardiac function and alleviated myocardial oxidative stress and injury. Overall, these results suggest that RET at mitochondrial complex I represents a potential therapeutic target in SICM and support the use of metformin as a promising strategy for preventing and treating septic myocardial dysfunction.

Keywords:  complex I; metformin; mitochondrial ROS; reverse electron transfer; sepsis-induced cardiomyopathy

DOI:  https://doi.org/10.3390/biology15151267