bims-mitmed 2026-08-23 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–08–23
fifteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.
Allosteric rewiring of mitochondrial stress signaling through Miro1.
Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).
Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.
Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.
Disease-mutations perturb proton transfer reactions in respiratory complex I.
Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.
Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.
The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.
A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.
Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
Human brain organoids record the passage of time over multiple years.
Nicotinamide mononucleotide combined glucose counteracts iron overload induced mitochondrial dysfunction in mice under hypobaric hypoxia.
A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.

Metabolomics. 2026 Aug 20. pii: 140. [Epub ahead of print]22(5):

Cross-species urinary metabolomics identifies 2-hydroxyisovalerate as a candidate biomarker for mtDNA-based disorders.

Marianne Venter, Karin Terburgh, Jeremie Z Lindeque, Emi Ogasawara, Mirian C H Janssen, Jan A M Smeitink, Kazuto Nakada, Roan Louw.

  Pathogenic mitochondrial DNA (mtDNA) mutations contribute to a broad spectrum of both common and rare metabolic diseases. However, clinical presentation is highly variable and only partially explained by the proportion of mutant mtDNA or heteroplasmy. With the relationship between mutation burden and clinical manifestation poorly defined, controlled models are required to uncover underlying mechanisms. Here, we explore the metabolic consequences of increasing heteroplasmy in a well-characterised mouse model harbouring a pathogenic mtDNA deletion. Untargeted urinary metabolomics reveals distinct mutation load-dependent metabolic shifts with some metabolites declining early on, while others exhibit threshold-like increases beyond ~ 60% mutation load - the level at which lactic acidemia and OXPHOS defects become apparent in this model. To assess translational relevance, we examined these heteroplasmy-associated metabolites in urine from patients carrying the most common mtDNA mutation, m.3243 A > G. Several of these metabolites were differentially expressed in patients relative to controls, with conserved directionality across species. Among these, 2-hydroxyisovalerate (2-HIVA), which was most strongly affected in the mouse model, also emerged as the top discriminator in patients. Receiver operating characteristic analysis indicated that urinary 2-HIVA has strong discriminatory power, supporting its potential utility as a biomarker for mtDNA-based disorders. These findings enhance our understanding of mtDNA-related disease pathophysiology and establish a foundation for further validation studies.

Keywords:  2-Hydroxyisovalerate; Heteroplasmy; M.3243A > G; Metabolomics; Mito-mice; Mitochondrial disease; MtDNA

DOI:  https://doi.org/10.1007/s11306-026-02518-1
Cell Chem Biol. 2026 Aug 20. pii: S2451-9456(26)00283-7. [Epub ahead of print]33(8): 1071-1073

Allosteric rewiring of mitochondrial stress signaling through Miro1.

Layla Drwesh, Julia C Fitzgerald.

In this issue of Cell Chemical Biology, Chandra and colleagues1 demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

DOI: https://doi.org/10.1016/j.chembiol.2026.07.011
Neurotherapeutics. 2026 Aug 18. pii: S1878-7479(26)00218-7. [Epub ahead of print] e01048

Use of nucleoside therapy for mitochondrial DNA depletion/deletion syndrome (MDDS).

Michio Hirano, Andres Berardo, Emanuele Barca, Valentina Emmanuele, Austin Larson, Antonella Spinazzola, Amel Karaa.



Keywords:  Nucleoside therapy, POLG, Thymidine, deoxycytidine, Thymidine kinase 2, TK2d

DOI:  https://doi.org/10.1016/j.neurot.2026.e01048
Hum Mol Genet. 2026 Aug 10. pii: ddag080. [Epub ahead of print]35(17):

Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts.

Paola Zanfardino, Alessandro Amati, Sharon Cox, Gennaro Agrimi, Stefano Doccini, Patricio Fernández-Silva, Apollonia Tullo, Jessica Rosati, Filippo M Santorelli, Vittoria Petruzzella.

  Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare autosomal recessive neuropathy caused by mutations in the MTMR5/SBF1 gene. In this study, we characterized dermal fibroblasts derived from a patient carrying compound-heterozygous MTMR5/SBF1 variants (R763H/G1064E) and identified alterations affecting mitochondrial metabolism and cellular stress pathways. Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved. In line with our previous evidence of enhanced mitophagy, these findings support the presence of altered mitochondrial quality control. The reduction in cellular energy production was not accompanied by increased glycolytic activity, indicating a metabolically quiescent phenotype. Transcriptomic profiling revealed dysregulation of the PI3K/AKT signalling pathway. AKT phosphorylation at Ser473 was increased in the absence of complete canonical AKT activation. These signalling changes were associated with increased expression of p53 and p21 and with features consistent with premature cellular senescence. Overall, our findings identify metabolic quiescence and premature senescence as previously unrecognized aspects of CMT4B3 cellular pathology and suggest that altered coordination between mitochondrial metabolism and intracellular signalling may contribute to disease pathogenesis.

Keywords:  Charcot–Marie–tooth disease type 4B3; MTMR5/SBF1; mitochondria; oxidative phosphorylation; senescence; transcriptomics

DOI:  https://doi.org/10.1093/hmg/ddag080
Ophthalmology. 2026 Aug 18. pii: S0161-6420(26)00586-5. [Epub ahead of print]

Late-onset Leber Hereditary Optic Neuropathy: disease triggers and prognostic factors in a large Italian cohort.

Marco Battista, Michele Carbonelli, Luigi Brotto, Giulia Amore, Catarina P Coutinho, Martina Romagnoli, Alice Galzignato, Paolo Nucci, Leonardo Caporali, Maria Lucia Cascavilla, Claudio Fiorini, Chiara La Morgia, Francesco Bandello, Valerio Carelli, Piero Barboni.

   PURPOSE: To characterize the clinical and genetic features, investigate disease triggers, and explore factors associated with visual recovery in late-onset Leber Hereditary Optic Neuropathy (LHON).
DESIGN: Retrospective cohort study.
SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Seventy-seven patients with late-onset LHON (onset ≥ 40 years of age) were identified from a larger cohort of 398 Italian LHON patients. Full clinical and genetic analyses were performed on 67 of these patients, while an internal control group of 562 healthy individuals was utilized for mitochondrial haplogroup comparisons.
METHODS, INTERVENTION, OR TESTING: Patient medical records were retrospectively reviewed to assess demographics, environmental exposures (smoking history), hormonal status (menopause, hormonal therapy), systemic comorbidities, and idebenone treatment data. Genetic testing evaluated primary mitochondrial DNA (mtDNA) mutations, mitochondrial haplogroups, and NQO1 polymorphisms. Statistical relationships were investigated using an exploratory chi-square automatic interaction detection (CHAID) analysis to generate hypothesis-generating decision tree models.
MAIN OUTCOME MEASURES: The primary outcome measures were the identification of precipitating factors (disease triggers) for LHON conversion and the rate of visual recovery, which was defined as an improvement of at least 0.3 LogMAR or a change from off-chart to on-chart visual acuity.
RESULTS: The m.11778G>A variant was the predominant mtDNA mutation (62.7%), and the male-to-female ratio was lower than in canonical LHON (1.48:1). Smoking history was present in 58.2% of patients, and 85.2% of women were postmenopausal. Other relevant factors included primary open-angle glaucoma (6%) and the LHON 'plus' phenotype (7.5%). The overall visual recovery rate was 38.8%. Exploratory CHAID analysis suggested that idebenone treatment at a dosage of ≥900 mg/day and the presence of a J or T mitochondrial haplogroup were associated with a higher probability of visual recovery.
CONCLUSIONS: Late-onset LHON represents a clinically relevant subset in which environmental and hormonal factors may contribute to disease conversion. In this retrospective cohort, high-dose idebenone treatment was associated with a higher probability of visual recovery, particularly among patients with a J or T haplogroup background. These exploratory findings should be considered hypothesis-generating and warrant confirmation in prospective studies.

Keywords:  Leber Hereditary Optic Neuropathy; haplogroups; idebenone; late-onset disease; mitochondria

DOI:  https://doi.org/10.1016/j.ophtha.2026.08.017
Biochim Biophys Acta Bioenerg. 2026 Aug 17. pii: S0005-2728(26)00022-8. [Epub ahead of print] 149602

Disease-mutations perturb proton transfer reactions in respiratory complex I.

Patricia Saura, Sofia Badolato, Andrea Gangdal, Adel Beghiah, Ville R I Kaila.

  Respiratory Complex I powers oxidative phosphorylation by a long-range proton-coupled electron transfer (PCET) reaction, with mutations linked to more than half of all human mitochondrial disorders. Yet, the molecular principles underlying the functional impairment remain difficult to test, as most mutations impede both the proton pumping and oxidoreductase activities due to the tightly coupled PCET process. Here, we probe how key disease mutations in the terminal ND5 subunit (NuoL/Nqo12), linked to the development of Leigh's syndrome (LS) and LHON/MELAS (F124L, M252T, D393N), affect the proton transport activity within the dissected antiporter module Nqo12. All constructs result in fully folded antiporter modules, with the introduced substitutions showing enhanced proton conduction rates across the proteoliposome membranes relative to the wild type module. Our molecular dynamics simulations reveal that the mutations perturb the internal water network and ion-pair dynamics that are central for the long-range PCET activity in Complex I. Taken together, we suggest that the mitochondrial disease mutations alter the redox-driven proton pumping activity of Complex I by perturbing the function of local proton gates, and result in an uncontrolled proton translocation across the antiporter module. The molecular consequences of disease mutations are discussed in the context of the proposed pumping mechanism.

Keywords:  Cellular respiration; LHON, MELAS; Leigh syndrome; Mitochondrial disease; Molecular mechanism

DOI:  https://doi.org/10.1016/j.bbabio.2026.149602
Neurol Sci. 2026 Aug 20. pii: 719. [Epub ahead of print]47(9):

Giant panda sign: an adult case of single large-scale mitochondrial DNA deletion syndrome.

Li-Ping Zhao, Qi-Dong Tang, Qu Li.

  A 38-year-old man presented with long-standing bilateral ptosis and new-onset paroxysmal limb weakness, which improved transiently after steroid treatment. He developed lethargy after self-discontinuation of medication. Brain MRI revealed the classic giant panda sign in the midbrain. Elevated plasma lactate and lactate peak on MRS were detected. Genetic testing identified a 7424 bp large-scale mitochondrial DNA deletion, confirming the diagnosis of single large-scale mitochondrial DNA deletion syndrome. Although the giant panda sign is classically associated with Wilson's disease, this case highlights that this characteristic imaging finding warrants mitochondrial genetic screening in adults with ophthalmoplegia and hyperlactatemia.

Keywords:  Giant panda sign; Magnetic resonance imaging; Single Large-Scale Mitochondrial DNA Deletion Syndrome

DOI:  https://doi.org/10.1007/s10072-026-09325-5
Neuromuscul Disord. 2026 Aug 13. pii: S0960-8966(26)01063-1. [Epub ahead of print]67 107395

Identification of a novel likely pathogenic MT-TS2 variant in a patient with mitochondrial myopathy, retinitis pigmentosa and sensorineural hearing loss.

Madalena Couto, Mafalda Delgado Soares, Pedro Coelho, Rafael Roque, Marisa Brum.

  Mitochondrial diseases are a prevalent cause of metabolic disorders arising from nuclear or mitochondrial DNA mutations. Their clinical and genetic heterogeneity highlight their diagnostic complexity. A 55-year-old male patient with Kallmann syndrome, retinitis pigmentosa and congenital sensorineural hearing loss presented with a one-year history of generalized weakness and imbalance. Examination revealed generalized muscle atrophy, hyporeflexia, and mild tetraparesis. Following an electromyography suggestive of proximal myopathy, muscle biopsy was consistent with mitochondrial myopathy. Mitochondrial respiratory chain analysis demonstrated increased activity of complex II and residual increases in complex I and cytochrome C. Full mitochondrial DNA sequencing identified a heteroplasmic MT-TS2 variant (m.12257G>A), with 15% heteroplasmy in blood and nearly 100% in muscle tissue. This variant was classified as likely pathogenic. This case illustrates a new potentially pathogenic variant in the MT-TS2 gene. Comprehensive analysis of mitochondrial DNA is essential to establish a definitive diagnosis.

Keywords:  MT-TS2 gene; Mitochondrial myopathy; Novel potentially pathogenic variant

DOI:  https://doi.org/10.1016/j.nmd.2026.107395
Hum Reprod Update. 2026 Aug 19. pii: dmag022. [Epub ahead of print]

The role of mitochondrial dysfunction and genetics in female infertility and premature ovarian insufficiency.

Brianna L Kline, Alison G Compton, Ann E Frazier, Svenja Pachernegg, Andrew H Sinclair, Katie L Ayers, Elena J Tucker.

   BACKGROUND: Female infertility occurs in ∼37% of infertile couples, while premature ovarian insufficiency (POI) impacts 1-3.7% of women under the age of 40. POI is clinically heterogeneous, with various genetic pathways associated with its pathogenesis. Mitochondrial diseases (MDs) are a broad group of clinically heterogeneous genetic conditions characterized by aberrantly functioning mitochondria. MDs have a disproportionate burden on organs and tissues with increased aerobic/energy demands, such as the heart, skeletal muscles, brain, and ovaries. The role of mitochondria in female fertility and ovarian reserve is increasingly being recognized.
OBJECTIVE AND RATIONALE: A comprehensive understanding of the role of mitochondria in the maintenance of female fertility is pertinent to better understanding female reproductive potential. In a world with increasing demand for assisted reproductive technologies (ART), due to a considerable rate of global infertility, there is a need to better understand the genes and pathways involved in female reproduction. This review summarizes, evaluates, and explores the current knowledge of mitochondria-associated genes and variants that are implicated in POI, including their function and dysfunction in female reproduction.
SEARCH METHODS: We searched articles in the PubMed database, containing the following key words: premature ovarian insufficiency, mitochondria, mitochondrial, premature ovarian failure, genetics, mitochondrial DNA, mtDNA, mitochondrial protein, infertility, premature menopause, mitochondrial donation, assisted reproductive technologies, electron transport chain, oxidative phosphorylation (OXPHOS), mitochondrial disease, oocyte, oogenesis, meiosis, in vitro fertilization, mitoribosome, Perrault syndrome, and ovarioleukodystrophy, in the English-language literature until March 2026.
OUTCOMES: Genetic variants that affect mitochondrial genes/proteins can negatively impact ovarian function. Various mitochondrial pathways are associated with female infertility, reflecting the broad sensitivity of ovarian reserve to mitochondrial dysfunction. Mitochondrial dysfunction and infertility can present in isolation or as part of a syndrome. Infertility in women may be the first clinical sign of a MD. Conversely, POI may be an underappreciated symptom of MDs.
WIDER IMPLICATIONS: This review draws attention to the fact that females with MDs should be monitored for POI so it can be detected early for prompt and appropriate therapeutic interventions, such as hormone replacement therapy. This is known to mitigate the risk of comorbidities such as cardiovascular and bone disease and will optimize long-term health outcomes. Of equal importance, our review highlights the potential for girls and women presenting with apparently 'isolated' POI to harbour pathogenic variants in MD-associated genes, therefore putting these individuals at risk of developing further clinical manifestations of MDs. We emphasize the need for surveillance in these cases for hearing loss, vision disturbance, cardiomyopathy, muscle weakness and neurodegeneration, depending on the genetic cause. Given that mitochondrial function is essential to female fertility, future therapies for mitochondria-associated infertility could involve mitochondrial supplementation to improve the mitochondrial fraction or mitochondrial donation to optimize the likelihood of reproductive success. Finally, we also discuss the current landscape of biomarkers as potential early diagnostic tools for POI. Whilst currently rudimentary in their clinical utility, the further development of early screening methods will be invaluable for the detection, diagnosis, and early intervention of POI.
REGISTRATION NUMBER: N/A.

Keywords:  POI; genetics; infertility; mitochondria; mitochondrial disease; premature ovarian insufficiency

DOI:  https://doi.org/10.1093/humupd/dmag022
Pediatr Neurol. 2026 Jul 31. pii: S0887-8994(26)00243-2. [Epub ahead of print]184 9-10

A Heterozygous Pathogenic Variant in POLG Associated With Isolated Neuropathic Pain and Rhabdomyolysis.

Phan Q Duy, Weilai Dong, Avram Bukhbinder, Danielle B Pier.



Keywords:  Mitochondrial disease; Neuropathy; POLG; Rhabdomyolysis

DOI:  https://doi.org/10.1016/j.pediatrneurol.2026.07.033
Sci Adv. 2026 Aug 21. 12(34): eaed6318

Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.

Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.

Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.

DOI: https://doi.org/10.1126/sciadv.aed6318
Extracell Vesicle. 2026 Jun;pii: 100100. [Epub ahead of print]7

Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.

Paromita Paul Pinky, Zhong-Min Wang, Purva Khare, Jhanvi R Jhaveri, Abigail Sullivan, Vivek Basudkar, Krithika S Rao, Audrey Lawrence, Adithri Pingali, Kandarp M Dave, Donna B Stolz, Ming Sun, Si-Yang Zheng, Sruti S Shiva, Carol Milligan, Osvaldo Delbono, Devika S Manickam.

  Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1G93A transgenic mouse model of ALS.

Keywords:  ALS; EVs; extracellular vesicles; large EVs; mitochondria; motor neurons; small EVs; spinal cord

DOI:  https://doi.org/10.1016/j.vesic.2025.100100
Nature. 2026 Aug 19.

Human brain organoids record the passage of time over multiple years.

Irene Faravelli, Noelia Antón-Bolaños, Anqi Wei, Tyler Faits, Abhishek Sampath Kumar, Sophia Andreadis, Rahel Kastli, Marta Montero Crespo, Mara Steiger, Daniel Leible, Elizabeth Zhang, Bobae An, Yaron Meirovitch, Sayara Silwal, Sung Min Yang, Alexander Kovacsovics, Xian Adiconis, Helene Kretzmer, Joshua Z Levin, Edward S Boyden, Jeff Lichtman, Aviv Regev, Alexander Meissner, Paola Arlotta.

The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models1. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro. The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture.

DOI: https://doi.org/10.1038/s41586-026-10877-x
Mol Cell Proteomics. 2026 Aug 21. pii: S1535-9476(26)00144-1. [Epub ahead of print] 101648

Nicotinamide mononucleotide combined glucose counteracts iron overload induced mitochondrial dysfunction in mice under hypobaric hypoxia.

Fancheng Tan, Xiaoyun Huang, Xiaoya Mao, Yanyi Wang, Xingyao Wang, Feitai Tang, Xing Chen, Ridong Mao, Xiaoyu Gong, Lin Chen, Li-Jun Di, Shen Zhang, Jun Zeng, Shu-Hai Lin.

Extreme high-altitude environment poses severe threats to human health, underscoring the urgent need for effective, safe metabolic interventions. Here, we demonstrate that combined regimen of nicotinamide mononucleotide (NMN) and glucose attenuates tissue injury and prevents body weight loss in mice under hypobaric hypoxia (HH). By leveraging a multi-tissue integrative atlas encompassing metabolome, lipidome, proteome, and phenotypic profiles, we identified HH-induced iron overload and oxidative stress as key pathological drivers. NMN plus glucose supplementation significantly counteracted metabolic disruptions across multiple tissues. Mechanistically, HH induced transferrin-inspired iron delivery, causing iron overload and oxidative stress, along with glutathione depletion and lipid peroxidation across multiple tissues. Notably, we observed no significant changes in the protein levels of ferroptotic markers including ACSL4, GPX4, and FSP1, although cannot rule out the possibility of activity alterations of these proteins. Nevertheless, NMN combined with glucose effectively reversed the ferroptosis-associated metabolic alterations and alleviated mitochondrial dysfunction. Collectively, our study provides a systems-level metabolic atlas and reveals that NMN combined glucose mitigates HH-induced multi-organ injury by suppressing ferroptosis through metabolic reprogramming, offering a therapeutic potential for high-altitude hypoxia.

DOI: https://doi.org/10.1016/j.mcpro.2026.101648
Alzheimers Dement. 2026 Aug;22(8): e71680

A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD+-mitophagy axis on aging and neurodegeneration.

Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang.

   INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.

Keywords:  AD; ALS; HD; NAD+; PD; PandaOmics; aging; artificial intelligence; machine learning; mitophagy

DOI:  https://doi.org/10.1002/alz.71680