bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2026–03–29
twenty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation.
  2. Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
  3. Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
  4. Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
  5. Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.
  6. Regulation of skeletal muscle mitochondrial fuel utilization during exercise.
  7. Mitochondrial interplay with membrane organelles in health and disease.
  8. Cell biology: Killing the prisoner escaping from mitochondria.
  9. Mitochondrial DNA Modification in Assisted Reproduction: Concept to Practice-A Narrative Review.
  10. A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
  11. Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
  12. First atlas of brain organization shows development over a lifetime.
  13. Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
  14. Myo-inositol elevation as an in vivo marker of reactive gliosis in pediatric Friedreich ataxia: evidence from HERMES-edited MR spectroscopy.
  15. The expanding role of mitochondria-lipid droplet contacts in liver and their disruption by MASLD.
  16. Mitochondrial lactate venting limits oxidative stress.
  17. Mitochondrial Dysfunction in Renal Aging: A Vicious Cycle Driving Kidney Disease Progression.
  18. Mitochondrial perspectives on environmental pollutant-induced male reproductive toxicity.
  19. Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
  20. Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
  1. Stem Cell Res. 2026 Mar 16. pii: S1873-5061(26)00062-0. [Epub ahead of print]93 103966
    Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation.
    Pouiré Yameogo, Brandon J Gerhart, Monica F Sentmanat, Amber Neilson, Xiaoxia Cui, Mayank Verma, David R Lynch, Jill S Napierala, Marek Napierala.
      Friedreich's ataxia (FRDA) is a multisystem, autosomal recessive disease caused by biallelic expansion of GAA repeats in intron 1 of the frataxin gene (FXN). While ∼96% of FRDA patients carry expanded GAA repeats on both FXN alleles, ∼4% are compound heterozygous with expanded GAA repeats on one allele and another mutation on the second allele. We generated induced pluripotent stem cells from blood lymphocytes from a FRDA patient carrying the FXN c.165 + 5G > C point mutation, which interferes with canonical splicing of intron 1 of the FXN gene. These cells allow for development of therapeutic approaches that target splicing defect in FRDA.
    DOI:  https://doi.org/10.1016/j.scr.2026.103966
  2. Autophagy. 2026 Mar 22. 1-2
    Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
    Julia A Thayer, Derek P Narendra.
      Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
    Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2646238
  3. Eur J Neurol. 2026 Mar;33(3): e70554
    Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE-Like Features.
    Giuliana Capece, Luca Caumo, Sara Volta, Pietro Riguzzi, Elena Sogus, Angela Petrosino, Sara Vianello, Daniele Sabbatini, Leonardo Salviati, Renzo Manara, Carlo Viscomi, Gianni Sorarù, Luca Bello, Elena Pegoraro.
       BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive disease caused by variants in the thymidine phosphorylase gene (TYMP), primarily characterized by severe gastrointestinal and neurological symptoms. The complete phenotype of MNGIE has not been linked to any gene other than TYMP.
    METHODS: We describe two identical twins who exhibited delayed psychomotor development, infantile bilateral cataract, congenital demyelinating polyneuropathy, and severe progressive gastrointestinal dysmotility with recurrent pseudo-obstruction episodes, along with diffuse supratentorial leukoencephalopathy that mainly overlaps with classic TYMP-related MNGIE. During the course of the disease, one patient developed Wernicke encephalopathy, triggered by chronic malnutrition related to recurrent gastrointestinal pseudo-obstruction. This patient later suffered from a catastrophic stroke-like episode, resulting in massive cerebral edema and brain death at the age of 38.
    RESULTS: Next-generation sequencing (NGS) using a custom-targeted mitochondrial gene panel identified two compound heterozygous variants in the POLG gene: the paternal variants p.Thr251Ile and p.Pro587Leu, occurring in cis, and the novel maternal variant p.Arg853Gly. Quantification of mtDNA by real-time PCR on skeletal muscle DNA detected significant depletion, but no multiple deletions were detected with mtDNA analysis by long-range PCR and Nanopore sequencing.
    CONCLUSIONS: These cases showed a very distinctive POLG phenotype, with some MNGIE-like features, expanding the clinical and genetic spectrum of the POLG-related diseases. Additionally, they highlighted the importance of monitoring for thiamine deficiency in mitochondrial patients with severe gastrointestinal dysmotility who experience sudden clinical deterioration.
    Keywords:  central nervous system diseases; malabsorption syndromes; mitochondrial diseases; mitochondrial encephalomyopathies
    DOI:  https://doi.org/10.1111/ene.70554
  4. EMBO J. 2026 Mar 24.
    Stress-induced OMA1-mediated cleavage of AIFM1 suppresses cell growth by controlling mitochondrial OXPHOS activity.
    Mitsuhiro Nishigori, Serina Hirata, Hidetaka Kosako, Takeshi Ichinohe, Hendrik Nolte, Jan Riemer, Thomas Langer, Takumi Koshiba.
      Mitochondrial proteases regulate dynamic properties of organelle morphology and ensure functional plasticity at the cellular level. The metalloprotease OMA1 mediates constitutive and stress-inducible processing of its mitochondrial substrates, although only a few of its direct functional targets have been characterized. Using in vitro and in vivo multiproteomic and biochemical approaches, we here demonstrate that the membrane-anchored intermembrane space (IMS) protein AIFM1 serves as a mitochondrial stress-responsive OMA1 substrate. Under stress conditions, OMA1 cleaves AIFM1 in the IMS with slower kinetics than its conventional substrate, the dynamin-like GTPase OPA1. OMA1-mediated dislocation of cleaved AIFM1 from the mitochondrial inner membrane reduces its interaction with oxidative phosphorylation subunits, thereby decreasing respiratory activity and impairing cell growth. Furthermore, we reveal that under steady-state conditions AIFM1 broadly safeguards the mitochondrial proteome by mediating the import of proteins, particularly respiratory complex I subunits, via the TIM23 complex. Similar changes to the mitochondrial proteome occur in the lungs of virally infected mice, accompanied by stress-inducible AIFM1 processing. These findings identify OMA1 as a key integrator of mitochondrial stress and cellular energetics through AIFM1 remodeling.
    Keywords:  AIFM1; Mitochondrial Stress; OMA1; OXPHOS Activity; Proteolysis
    DOI:  https://doi.org/10.1038/s44318-026-00734-y
  5. Neurol Genet. 2026 Apr;12(2): e200368
    Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.
    Alessandra Rocco, Christian Laurini, Yuri Matteo Falzone, Silvia Calzavara, Ubaldo Del Carro, Stefano Carlo Previtali, Francesca Maltecca.
       Objectives: The AFG3L2 gene encodes a mitochondrial AAA-protease involved in inner mitochondrial membrane (IMM) proteostasis. Heterozygous variants in the AFG3L2 proteolytic domain cause Spinocerebellar Ataxia type 28, heterozygous variants in the AFG3L2 ATPase domain cause Optic Atrophy type 12, while biallelic variants lead to recessive Spastic Ataxia type 5. In this study, we aimed to investigate the link between AFG3L2 haploinsufficiency and Charcot-Marie-Tooth (CMT) phenotypes.
    Methods: We performed clinical evaluation, genetic analyses, electrophysiology, and functional studies in 1 patient's fibroblasts.
    Results: In this study, we report a patient presenting with progressive symmetric distal muscle atrophy, weakness, pes cavus, and sensory deficits at lower limbs, in the absence of cerebellar or pyramidal signs. Electrophysiologic studies confirmed axonal sensorimotor neuropathy. After excluding common CMT-related genes, clinical exome sequencing revealed a heterozygous truncating variant in AFG3L2 [NM_006793.3:c.121C > T; p.(Arg41*)]. In patient's fibroblasts, we observed ∼50% reduction in AFG3L2 protein levels, which is sufficient to hyperactivate the stress-sensitive IMM protease OMA1. Consequently, we detected increased OPA1 processing, mitochondrial shortening, and activation of the integrated stress response.
    Discussion: These findings suggest that AFG3L2 haploinsufficiency can underlie axonal CMT, expanding the clinical spectrum of AFG3L2-related diseases and emphasizing its potential inclusion in CMT diagnostic panels.
    DOI:  https://doi.org/10.1212/NXG.0000000000200368
  6. Trends Endocrinol Metab. 2026 Mar 24. pii: S1043-2760(26)00014-7. [Epub ahead of print]
    Regulation of skeletal muscle mitochondrial fuel utilization during exercise.
    Likun Yang, Tingting Fu, Hao Yu, Yujing Yin, Zhenji Gan.
      Skeletal muscle exhibits remarkable metabolic plasticity, with mitochondria playing a central role in adapting to energy demands during exercise. These organelles form a dynamic and specialized system capable of remodeling to meet metabolic challenges. Recent studies demonstrate that exercise not only stimulates mitochondrial biogenesis but also engages finely tuned quality-control mechanisms to sustain energy efficiency and performance. A key adaptation is mitochondrial fuel flexibility, the capacity to switch between lipid and carbohydrate oxidation, which underlies endurance and metabolic health. Importantly, efficient lipid utilization, rather than low lipid content, explains why trained muscle can accumulate lipids while remaining insulin sensitive. Here, we review emerging insights into how exercise reprograms skeletal muscle mitochondria to optimize fuel use and highlight implications for metabolic disease.
    Keywords:  biogenesis; exercise; fuel utilization; mitochondria; mitochondrial quality control; skeletal muscle
    DOI:  https://doi.org/10.1016/j.tem.2026.01.014
  7. Cell Commun Signal. 2026 Mar 27.
    Mitochondrial interplay with membrane organelles in health and disease.
    Shao-Hong Liu, Yong Wang, Chao Tong, Xiao-Man Liu.
      
    Keywords:  ERMCS; Endoplasmic reticulum (ER); Endosomes; Lipid droplets; Lysosomes; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-026-02843-x
  8. Curr Biol. 2026 Mar 23. pii: S0960-9822(26)00166-1. [Epub ahead of print]36(6): R259-R261
    Cell biology: Killing the prisoner escaping from mitochondria.
    Arun Kumar Kondadi, Andreas S Reichert.
      Mitochondria contain their own DNA (mtDNA), which can be released via multiple routes and cause inflammation and disease. A recent study revealed the unexpected role of a mitochondrial nuclease, present in the intermembrane space, in preventing mtDNA escape via mitophagy.
    DOI:  https://doi.org/10.1016/j.cub.2026.02.016
  9. Int J Mol Sci. 2026 Mar 23. pii: 2890. [Epub ahead of print]27(6):
    Mitochondrial DNA Modification in Assisted Reproduction: Concept to Practice-A Narrative Review.
    Mariam Mehwish Mohsin, Misbah Azher, Fatima Asghar, Hiba Habeebu Rahiman, Rajani Dube, Subhranshu Sekhar Kar, Shadha Nasser Mohammed Bahutair, Bellary Kuruba Manjunatha Goud, Swayam Siddha Kar.
      Mitochondria play a fundamental role in human reproduction by supplying the energy required for key early reproductive processes. As mitochondrial Deoxyribonucleic acid (mtDNA) is maternally inherited, pathogenic mutations can lead to multisystem disorders that are transmitted to offspring. Mitochondrial replacement therapy (MRT) has emerged as a promising assisted reproductive approach to prevent the transmission of pathogenic mtDNA by replacing defective mitochondria with healthy donor mitochondria. There have been recent reports of successful MRT in humans. However, MRT remains a relatively new procedure and needs further experiments to establish its long-term safety and effectiveness. Overall, mitochondrial replacement therapy holds significant promise in helping families build healthier futures. This review explores the evolution of mitochondrial DNA modification in reproductive cells and addresses the associated ethical considerations, including acceptable clinical indications, reproductive choices, and long-term considerations for affected children.
    Keywords:  DNA modification; assisted reproductive technique; mitochondria; mitochondrial diseases; mitochondrial replacement therapy
    DOI:  https://doi.org/10.3390/ijms27062890
  10. Nat Commun. 2026 Mar 27.
    A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
    Emir Maldosevic, Radoslaw Jakub Gora, Liangguang Leo Lin, Linyao Elina Zhou, Zexin Jason Li, Yelena Peskova, Ling Qi, Shu-Ou Shan, Ahmad Jomaa.
      The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identify a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increase NAC barrel dynamics and reduce its binding to the ribosome. This impairs the ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing mechanistic insights into protein targeting fidelity with broader implications for cellular proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-71061-3
  11. Cell Death Dis. 2026 Mar 24.
    Malic enzyme 2 suppresses PINK1-Parkin-mediated mitophagy by stabilizing ATAD3A via competitive interaction with TRIM25.
    Qian Liu, Lei Su, Xiaoyun Wei, Shijie Lin, Lingkai Huang, Lige Hou, Yanhong Wang, Liubing Hu, Junyang Tan, Jing Qiao, Qinghua Zhou, Yi Ma, Wenjun Wang, Jianshuang Li.
      Malic enzyme 2 (ME2), a pivotal enzyme related to the tricarboxylic acid (TCA) cycle, has been implicated in multiple cancers due to its overexpression and metabolic role in regulating the NADP+/NADPH balance. Malic enzyme 2 has been reported to regulate mitochondrial biogenesis and fusion; however, whether malic enzyme 2 participates in mitophagy regulation has remained unclear. Here, we reported that malic enzyme 2 depletion enhances PINK1-Parkin-mediated mitophagy. Mechanistically, ME2 competes with the E3 ubiquitin ligase TRIM25, disrupting its binding with ATPase family AAA domain-containing protein 3 A (ATAD3A), a mitochondrial protein crucial for the degradation of PINK1. Loss of malic enzyme 2 strengthens the TRIM25-ATAD3A interaction, resulting in ATAD3A ubiquitination and proteasomal degradation. The consequent PINK1 accumulation drives mitophagy activation. Hyperactivated mitophagy caused by malic enzyme 2 knockdown disrupts mitochondrial homeostasis, which suppresses the proliferative capacity of hepatoma cells. Moreover, pharmacological inhibition of mitophagy partially rescued the suppressed cell proliferation in the malic enzyme 2-knockdown cells. Our findings reveal a previously unrecognized role of malic enzyme 2 in mitochondrial quality control and highlight the ME2-ATAD3A-PINK1 axis as a potential regulatory node for mitophagy modulation.
    DOI:  https://doi.org/10.1038/s41419-026-08623-2
  12. Nature. 2026 Mar 25.
    First atlas of brain organization shows development over a lifetime.
    Gemma Conroy.
      
    Keywords:  Brain; Developmental biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-00975-1
  13. Science. 2026 Mar 26. 391(6792): eadz6830
    Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
    Christopher J Cowley, Sairaj M Sajjath, Luis F Soto-Ugaldi, Mara Steiger, Samantha B Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A U Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe'er, Elaine Fuchs.
      Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
    DOI:  https://doi.org/10.1126/science.adz6830
  14. Neuroimage Clin. 2026 Mar 03. pii: S2213-1582(26)00042-2. [Epub ahead of print]50 103983
    Myo-inositol elevation as an in vivo marker of reactive gliosis in pediatric Friedreich ataxia: evidence from HERMES-edited MR spectroscopy.
    William Gaetz, Muhammad G Saleh, Charlotte Birnbaum, Luke Bloy, Timothy P L Roberts, David R Lynch.
       BACKGROUND: Friedreich ataxia (FRDA) is a rare neurodegenerative disorder caused by frataxin deficiency and is characterized by mitochondrial dysfunction, oxidative stress, and progressive motor dysfunction. Most in vivo MRS work in FRDA has focused on the cerebellum, brainstem/pons, and spinal cord, consistently reporting abnormalities in the neuronal marker N-acetylaspartate (NAA) and the glial metabolite myo-inositol (mI). To our knowledge, the NAA/mI ratio in the primary motor cortex has not been reported in FRDA, particularly in pediatric cohorts. Additionally, in vivo edited MRS measurements of the inhibitory neurotransmitter γ-aminobutyric acid (GABA+ (GABA + macromolecular contributions)) in FRDA have not yet been reported and GSH has been examined only rarely in FRDA and, to our knowledge, has not been studied in the motor cortex in either adult or pediatric cohorts.
    OBJECTIVE: To assess GSH, GABA+, NAA, and mI across cerebellum and motor cortices in pediatric FRDA using HERMES-edited MRS.
    METHODS: We acquired HERMES MRS data from 16 children with FRDA and 15 age-matched controls. Tissue-corrected metabolite estimates were obtained using LCModel and voxel-based tissue segmentation. Linear mixed models (LMMs) were used to evaluate group and region effects, with subject as a random effect.
    RESULTS: LMMs revealed no significant group differences in tissue-corrected GSH or GABA + . In contrast, the tNAA/mI ratio was significantly reduced in FRDA (p < 0.001), driven by elevated mI (p < 0.001), while tNAA did not differ between groups (p = 0.150). ROI-specific analyses showed higher mI in FRDA in both motor cortices after Bonferroni correction, with a non-significant trend in cerebellum (pcorr = 0.054).
    CONCLUSIONS: These findings support a model of early reactive gliosis in pediatric FRDA, indexed by elevated mI and occurring without statistically significant neuronal loss, (acknowledging that significant reductions in tNAA may require larger samples to resolve), and extend prior cerebellar-focused work to the primary motor cortex. While GSH and GABA + did not differ between groups, the observed mI elevations highlight myo-inositol as a practical in vivo biomarker of astrocytic activation and a candidate marker for disease progression in FRDA. Longitudinal studies are needed to confirm its sensitivity to clinical trajectory and therapeutic response.
    Keywords:  Friedreich ataxia (FRDA); Glutathione (GSH); HERMES editing; Magnetic resonance spectroscopy (MRS); Myo-inositol (mI); γ-Aminobutyric acid (GABA)
    DOI:  https://doi.org/10.1016/j.nicl.2026.103983
  15. Nat Metab. 2026 Mar;8(3): 527-528
    The expanding role of mitochondria-lipid droplet contacts in liver and their disruption by MASLD.
    Jessica Segalés, Marc Liesa.
      
    DOI:  https://doi.org/10.1038/s42255-026-01483-2
  16. Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]
    Mitochondrial lactate venting limits oxidative stress.
    Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.
      Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.
    Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
  17. Antioxid Redox Signal. 2026 Apr;44(10-12): 464-487
    Mitochondrial Dysfunction in Renal Aging: A Vicious Cycle Driving Kidney Disease Progression.
    Wenpei Yu, Qing Ouyang, Weicen Liu, Lu Jia, Bin Wang.
       SIGNIFICANCE: The aging of the global population is linked to an increase in age-related diseases. The kidneys undergo both structural and functional declines with age, and aging is a significant risk factor for kidney diseases. Mitochondrial dysfunction is recognized as a crucial factor affecting kidney aging. Although the importance of disrupted mitochondrial homeostasis in renal aging has gained increasing attention, the associations and causal mechanisms have not been systematically summarized.
    RECENT ADVANCES: Mitochondria are highly dynamic organelles that operate in various functions, including cell metabolism, redox regulation, cell division, and cell death, and are closely associated with both cell senescence and kidney diseases. Furthermore, aging is also associated with mitochondrial redox dysfunction, abnormal calcium homeostasis, impaired quality control (QC), and increased mitochondrial DNA (mtDNA) leakages. Mitochondrial dysfunction and cellular senescence may sustain a vicious cycle in renal injury. Several types of drugs show promising potential in alleviating renal injury by modulating mitochondria-related aging phenotypes.
    CRITICAL ISSUES: Dysregulated redox status, mitochondrial metabolic reprogramming, mtDNA abnormalities, impaired mitochondrial QC, and mitochondrial calcium overload are the factors that establish a self-perpetuating vicious cycle that promotes renal aging. In addition, the roles of mitochondria-associated senescence in both acute kidney injury and chronic kidney disease are examined and summarized, with potential differences and promising interventions targeting mitochondrial dysfunction and cell senescence also highlighted.
    FUTURE DIRECTIONS: Clinically available interventions specifically aimed at addressing mitochondrial aging remain underdeveloped and require further clinical trials. Future research should also focus on creating drugs that can precisely target mitochondrial senescence to prevent the progression of age-related kidney diseases. Antioxid. Redox Signal. 44, 464-487.
    Keywords:  acute kidney injury; cell senescence; chronic kidney disease; mitochondrial dysfunction; renal aging
    DOI:  https://doi.org/10.1177/15230864251410936
  18. Toxicology. 2026 Mar 24. pii: S0300-483X(26)00061-2. [Epub ahead of print] 154454
    Mitochondrial perspectives on environmental pollutant-induced male reproductive toxicity.
    Qiujian Feng, Zhuozhi Gong, Bin Yan, Boda Guo, Jun Guo, Shengjing Liu.
      With rapid industrialization and urbanization, environmental pollutants have emerged as a major threat to male reproductive health, and declining semen quality together with rising rates of male infertility has now become a global public health concern. Owing to its high energetic demand and specialized cellular organization, the testis is especially vulnerable to pollutants, with mitochondria serving as a principal target because they coordinate energy metabolism and apoptotic control. Here we synthesize evidence on how heavy metals, air pollutants, organic pollutants, endocrine disrupting chemicals, micro(nanoplastics), pesticides, and mycotoxins injure testicular mitochondria and the mechanisms involved. Current evidence indicates that these pollutants compromise spermatogenesis and androgen production via convergent mitochondrial pathways, including oxidative stress, metabolic disruption, mitochondria dependent apoptosis, imbalance of mitochondrial dynamics, suppressed biogenesis, and dysregulated mitophagy. Importantly, these mechanisms are not independent, since individual pathways may dominate under specific exposure scenarios, yet they can also intersect and mutually reinforce one another to generate a multistep cascading network that culminates in reproductive injury. Therefore, mitochondrial dysfunction represents a central convergent node through which pollutants drive male reproductive toxicity. Future work should prioritize low dose, long term, and mixture exposure models, integrate multi omics approaches with testicular organoid platforms, define key regulatory pathways, identify early biomarkers, and evaluate mitochondria targeted interventions to support environmental risk assessment and prevention of male reproductive injury.
    Keywords:  disordered energy metabolism; environmental pollutants; mitochondrial quality control; oxidative stress; reproductive toxicity; testicular mitochondria
    DOI:  https://doi.org/10.1016/j.tox.2026.154454
  19. Biomolecules. 2026 03 16. pii: 445. [Epub ahead of print]16(3):
    Mitochondrial ROS in Retinal Neurodegeneration: Thresholds, Quality Control Failure, and Precision Therapeutic Windows.
    Snježana Kaštelan, Antonela Gverović Antunica, Suzana Konjevoda, Zora Tomić, Ana Sarić, Marjan Kulaš, Lorena Kulaš, Emina Kujundžić Begović, Samir Čanović, Petra Kovačević, Mira Ivanković.
      Mitochondrial reactive oxygen species (mtROS) play a dual role in retinal physiology, acting as essential redox signalling mediators under homeostatic conditions but driving oxidative damage and neurodegeneration once regulatory thresholds are exceeded. Owing to the exceptionally high energetic demands of retinal neurons and supporting cells, even subtle perturbations in mitochondrial redox balance can precipitate progressive retinal dysfunction. Increasing evidence indicates that retinal neurodegenerative diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and inherited optic neuropathies, are characterised not by uniform oxidative stress, but by disease- and stage-specific mtROS signatures shaped by mitochondrial quality control capacity. This review synthesises current insights into the sources, regulation, and signalling functions of mtROS in the retina, with particular emphasis on threshold-dependent redox transitions, reverse electron transport, and the progressive failure of mitochondrial quality control mechanisms, including mitophagy, mitochondrial dynamics, and redox-responsive transcriptional networks. The limitations of non-selective antioxidant strategies are critically examined, highlighting why indiscriminate ROS suppression has yielded limited clinical benefit. In contrast, emerging therapeutic approaches aimed at recalibrating mitochondrial redox homeostasis, rather than abolishing physiological signalling, are discussed in the context of disease stage, metabolic state, and mitochondrial competence. By integrating redox biology with mitochondrial quality control and precision medicine concepts, this review proposes a unifying framework in which retinal neurodegeneration is governed by regulated mtROS signalling and the progressive exhaustion of mitochondrial resilience. This model defines critical therapeutic windows for mitochondria-targeted intervention and provides a framework for biomarker-guided patient stratification.
    Keywords:  mitochondria-targeted intervention; mitochondrial quality control; mitochondrial reactive oxygen species (mtROS); mitophagy; precision medicine; redox signalling; retinal ganglion cells; retinal neurodegeneration; reverse electron transport
    DOI:  https://doi.org/10.3390/biom16030445
  20. Nat Commun. 2026 Mar 24.
    Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
    Giulio Di Minin, Anna B Rüegg, Kevin Halter, Tobias Fuhrer, Tatjana Kleele, Nicola Zamboni, Anton Wutz.
      A hallmark of mammals is a diploid genome. Despite constraints from dosage compensation and imprinting, haploid embryonic stem cells can be established. However, rapid diploidization is observed in such cultures from mice, rats, and humans, limiting their use and indicating counterselection of a haploid genome. Here, we use metabolic profiling to discover that diploidization is triggered by an imbalance that arises from a smaller cytoplasmic volume and increased mitochondrial density. Reduced respiration causes a change in redox potential, leading to increased NADPH. Conversely, we demonstrate that NADPH oxidation in the mitochondria is sufficient to stabilize the haploid genome. We further show that the redox change leads to reduced AURORA kinase activation on chromosomes, connecting metabolic state to mitotic regulation. Our data, therefore, identify a mitochondrial metabolic imbalance as the root cause of diploidization and connect redox dysregulation to karyotypic instability.
    DOI:  https://doi.org/10.1038/s41467-026-70939-6
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