bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2026–05–10
53 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Global mitochondrial connectivity map reveals the landscape of yeast functional assemblies and conserved protein communities.
  2. DGUOK-related mitochondrial DNA depletion syndrome presenting with neonatal cholestasis without marked hyperlactatemia: A diagnostic pitfall.
  3. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  4. Mitochondrial mechanics nucleates axonal jamming and swelling.
  5. The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
  6. Current state of the art in the transmission of mitochondrial DNA pathogenic variants: reviewing preventive-therapeutic alternatives.
  7. Evaluation of PacBio Long-Read and PCR-Based Short-Read Sequencing for Mitochondrial DNA (mtDNA) Variant Detection, with an Emphasis on Detection and Quantification of mtDNA Deletion.
  8. Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
  9. How membranes shape up for lipid transfer.
  10. Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
  11. Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
  12. Commentary: Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
  13. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  14. Polarized mitochondrial respiratory chain complexes in synaptic mitochondria induced by plasticity signals.
  15. Synphilin-1 Is Essential for Cytoskeletal Integrity of Brain Ventricular Cilia and Mitochondrial Proteostasis.
  16. Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
  17. LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif.
  18. Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling.
  19. STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture.
  20. Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.
  21. Special packaging enables effective mitochondrial delivery.
  22. Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
  23. Enrichment of Rare Variants in Nuclear-Encoded Mitochondrial Metabolism Genes in Patients with Early-Onset or Familial Parkinson's Disease.
  24. Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
  25. Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
  26. Lactylation landscape of mitochondrial proteins in myocardial infarction.
  27. β-ureidopropionase deficiency mimicking Leigh syndrome associated with methylmalonic aciduria.
  28. Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
  29. Generation of an iPSC line IUFi004-A-13 with homozygous NDUFS1 mutation for the study of Leigh syndrome.
  30. Two Novel Variants in MT-RNR1 Gene Associated with Hereditary Optic Neuropathy: A Case Report.
  31. Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
  32. MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.
  33. Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
  34. Cryptic DNA sequences encode a temperature sensor to regulate mitochondrial suicide during neuronal differentiation.
  35. NMNAT2-SARM1 Axis Drives Redox Failure and Disrupts APP Processing in Neurons.
  36. An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.
  37. Mitochondrial Function and Dysfunction in Female Fertility: Biological Mechanisms, Genetic Determinants, and Therapeutic Opportunities - A Review.
  38. Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.
  39. Dynamic proximity networks of myosin-19 (Myo19) and its mitochondrial receptors Miro2 and metaxin-3.
  40. Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
  41. Investigation of mitochondrial inner membrane ion conductance by planar lipid bilayer electrophysiology.
  42. AXOLOTL: an accurate method for detecting aberrant gene expression in rare diseases using coexpression constraints.
  43. When membrane insertion sets the pace of mitochondrial translation.
  44. Loss of mitochondrial DNA helicase in retinal macroglia drives neovascular retinopathy.
  45. Human organoids: Fit for drug discovery?
  46. Succinate calls a time-out on pyrimidine biosynthesis.
  47. Membrane insertion of mitochondrial-encoded proteins regulates ribosome decoding speed.
  48. Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
  49. Mitochondrial fission factor regulates mitochondrial Ca2+ homeostasis and neuronal activity in AgRP neurons.
  50. Mitochondrial complex III deficiency nuclear type 2: a case report and analysis of clinical onset age-related phenotypic features.
  51. Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.
  52. Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.
  53. Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
  1. Nat Commun. 2026 May 05.
    Global mitochondrial connectivity map reveals the landscape of yeast functional assemblies and conserved protein communities.
    Matthew Jessulat, Sadhna Phanse, Hiroyuki Aoki, Kirsten Broderick, Qingzhou Zhang, Inês Gomes Castro, Noelle Alexa Novales, Sakib Abrar Hossain, Tatiana Saccon, Mohamed Taha Moutaoufik, Thomson Patrick Joseph, Shahreen Amin, Larrisa Hoell, Zoran Minic, Yury Bykov, Noga Preminger, Sahily Gonzalez Crespo, Jamie Snider, Ashkan Golshani, Igor Stagljar, Jose R Rodriguez-Medina, Catherine F Clarke, Maya Schuldiner, Mohan Babu.
      Mitochondria are essential organelles whose functions depend on coordinated multiprotein complexes, yet their composition and organization remain incomplete. Here, we present a large-scale map of mitochondrial protein complexes by integrating affinity purification of 740 endogenously GFP-tagged mitochondrial proteins with biochemical co-fractionation of mitochondrial extracts from yeast (Saccharomyces cerevisiae) grown under respiratory conditions. Mass spectrometry identifies 13,716 high-confidence protein associations and defines 556 heteromeric complexes, many previously unknown. These assemblies reveal factors involved in coenzyme Q6 biosynthesis, membrane contact sites, phospholipid transport, and coordination with the MICOS complex during respiration. We further link 538 assemblies to 294 candidate human disease genes and construct a conservation map of 852,146 predicted mitochondrial interactions across 271 genomes, and validate key predictions in human cell lines and mouse brain tissue. Together, this work provides a comprehensive mitochondrial interactome, assigning functions to poorly characterized proteins, and offering insights into mitochondrial biology and disease-associated assemblies.
    DOI:  https://doi.org/10.1038/s41467-026-72525-2
  2. Mol Genet Metab Rep. 2026 Jun;47 101314
    DGUOK-related mitochondrial DNA depletion syndrome presenting with neonatal cholestasis without marked hyperlactatemia: A diagnostic pitfall.
    Moe Li, Hideo Sasai, Hiroaki Taniguchi, Atsushi Ishida, Yuya Kuwabara, Hideki Matsumoto, Daisuke Terazawa, Tomohiro Kanayama, Tatsuhiko Miyazaki, Akira Hara, Kei Murayama.
      Mitochondrial DNA depletion syndrome (MTDPS) is a group of severe mitochondrial disorders caused by nuclear gene variants that affect mitochondrial DNA (mtDNA) replication and nucleotide synthesis. Deoxyguanosine kinase deficiency is one of the most common subtypes, typically presenting with liver dysfunction in infancy and having a poor prognosis. We report a case of MTDPS presenting with cholestasis and mild hyperlactatemia in the neonatal period, which complicated early diagnosis. Histopathological and genetic analyses established the diagnosis. The patient, a female born at 36 weeks and 1 day of gestation, weighing 2124 g, developed cholestasis, poor feeding, and failure to thrive. Hyperlactatemia was not evident at presentation but gradually increased during the clinical course. Based on suspected mitochondrial disease, mitochondrial cocktail therapy was initiated on day 64. Liver transplantation was not feasible owing to cardiac and neurological complications, and conservative treatment was continued. However, the patient died of multiple organ failure on day 89. Postmortem liver biopsy showed a markedly reduced mtDNA copy number (8.1% of control), and genetic testing revealed a homozygous c.609_610del (p.Tyr204fs) variant in the DGUOK gene (NM_080916.3), confirming the diagnosis of DGUOK-related MTDPS. This case highlights that hyperlactatemia may be absent or only mild in the early stages of MTDPS, making timely diagnosis challenging. Mitochondrial functional analysis and genetic testing should be considered early in infants with unexplained cholestasis and liver failure, regardless of the lactate levels.
    Keywords:  Cholestasis; Deoxyguanosine kinase deficiency; Hepatocerebral form; Liver transplantation; Mitochondrial DNA depletion syndrome; Mitochondrial diseases
    DOI:  https://doi.org/10.1016/j.ymgmr.2026.101314
  3. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  4. bioRxiv. 2026 Apr 25. pii: 2026.04.23.720276. [Epub ahead of print]
    Mitochondrial mechanics nucleates axonal jamming and swelling.
    Patrick S Noerr, Ahmed A Abushawish, Gulcin Pekkurnaz, Padmini Rangamani.
      Neuronal function requires precise spatial organization of mitochondria to meet localized energetic demand. However, the physical constraints governing mitochondrial transport in axons remain poorly defined. Bidirectional motor-driven trafficking inherently introduces the potential for collisions, but the implications of these interactions for transport failure and structural damage are not understood. Here, we develop an agent-based model that couples mitochondrial motility, morphology, and lifecycle dynamics to a deformable axonal boundary. We show that mitochondrial traffic jams emerge from a force balance between active propulsion and steric interactions, and that their severity is governed by organelle shape and mechanical properties. Elongated, mechanically rigid mitochondria remain aligned and are transported rapidly, whereas flexible, low-aspect-ratio mitochondria are prone to jamming and accumulation. Incorporating fission and fusion dynamics reveals that fission amplifies transport disruption by generating collision-prone populations, while fusion restores transport by producing anisotropic structures that navigate crowded environments more efficiently. Importantly, we find that sustained jamming generates mechanical stress on the axonal membrane, leading to deformation and swelling. Together, these results establish a physical framework linking mitochondrial dynamics to axonal integrity and provide testable predictions for how dysregulated fission-fusion balance can drive transport failure and structural pathology in neurons.
    Significance: 2Axonal deformation is implicated in myriad neurodegenerative conditions. Mitochondrial transport disruption is inextricably linked to axonal deformation and disease progression. Mechanistic understanding of the interplay between mitochondrial transport and axon stability remains opaque. Here, we developed an agent-based model of mitochondrial transport through axons. We found that mitochondria, driven to-ward presynapses for energy supply and toward the soma for repositioning or recycling, can collide, jam, and accumulate within axonal segments. The severity of jamming is sensitive to mitochondrial density as well as mechanical and morphological properties. Further, we found a balance between lifecycle dynamics including fission and fusion is paramount to maintaining homeostatic transport. Lastly, we predict that accumulated mitochondria can deform the axonal membrane, thereby elucidating a direct mechanical link between mitochondrial transport disruption and axonal deformation.
    DOI:  https://doi.org/10.64898/2026.04.23.720276
  5. J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128
    The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
    Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.
      Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.
    Keywords:  (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome
    DOI:  https://doi.org/10.1016/j.jbc.2026.113128
  6. J Assist Reprod Genet. 2026 May 05.
    Current state of the art in the transmission of mitochondrial DNA pathogenic variants: reviewing preventive-therapeutic alternatives.
    Marta Reguera-Cabezas, Felipe Martínez-Pastor, Cristina Soriano-Úbeda.
      This review analyzes strategies to prevent or reduce the transmission of diseases caused by pathogenic variants in mitochondrial DNA (mtDNA). Among these, we will focus on prenatal screening, preimplantation genetic testing, gene-editing techniques, other molecular tools, and selected heterologous mitochondrial replacement techniques (MRTs), explaining their status and the uncertainties surrounding their clinical application. After this analysis and review, we recognise the limitations of the efficacy of prenatal and preimplantation genetic testing for mitochondrial DNA pathogenic variants, the legal constraints on gene editing, and the status of mitochondrial replacement techniques. MRTs are a safe and possibly more effective alternative for preventing diseases caused by mitochondrial DNA pathogenic variants.
    Keywords:  Assisted reproduction; Genetics; Heteroplasmy; Mitochondrial diseases; Mitochondrial replacement
    DOI:  https://doi.org/10.1007/s10815-026-03888-0
  7. Int J Mol Sci. 2026 Apr 16. pii: 3562. [Epub ahead of print]27(8):
    Evaluation of PacBio Long-Read and PCR-Based Short-Read Sequencing for Mitochondrial DNA (mtDNA) Variant Detection, with an Emphasis on Detection and Quantification of mtDNA Deletion.
    Tanaya Jadhav, Matthew Aruta, Maria Alejandra Diaz-Miranda, Avery Zucco, Laura K Conlin, Ramakrishnan Rajagopalan, Jing Wang.
      Accurate detection of all types of mitochondrial DNA (mtDNA) variants, including single large-scale mtDNA deletions (SLSMDs) and multiple mtDNA deletions (MMDs), along with heteroplasmy quantification, is essential for Primary Mitochondrial Disease (PMD) diagnosis. This study compares amplification-free PacBio long-read sequencing (LRS) mtDNA analysis with long-range PCR-based targeted mtDNA sequencing by short-read sequencing (SRS) in terms of detection sensitivity and accuracy. In total, 17 samples, including 4 SLSMD cases (3 blood, 1 muscle), 9 MMD muscle samples, and 4 deletion-negative controls (1 blood, 3 muscle), were sequenced using the PacBio Sequel IIe. Our findings demonstrate LRS's efficacy in detecting single nucleotide variants (SNVs) and large mtDNA deletions with precise breakpoints. LRS can accurately detect and distinguish SLSMD from MMD, providing deletion heteroplasmy without the need for a second methodology. Deletion heteroplasmy computed from LRS was highly correlated with the Droplet Digital PCR (ddPCR) estimates (Pearson's r2 = 0.95). While LRS can detect SNVs with approximately 5% heteroplasmy, only variants exceeding 10% heteroplasmy can attain 100% sensitivity, specificity, and precision when compared to those previously identified through clinical testing. In conclusion, our findings establish PacBio LRS as a robust tool for comprehensive mtDNA analysis capable of accurately detecting and quantifying heteroplasmic mtDNA variants and complex deletions.
    Keywords:  heteroplasmy; long-read sequencing; mitochondria DNA; mtDNA deletions; primary mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms27083562
  8. Int J Mol Sci. 2026 Apr 16. pii: 3557. [Epub ahead of print]27(8):
    Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
    Luminita Labusca, Teodor Stefan Gheorghevici, Bogdan Puha.
      Beyond their classical role as "cellular powerhouses", mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics-including fusion-fission balance, mitophagy-biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion-contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions.
    Keywords:  aging; intercellular mitochondrial communication; mitochondria; mitophagy; myocardial aging; neurodegeneration; skeletal muscle aging
    DOI:  https://doi.org/10.3390/ijms27083557
  9. Elife. 2026 May 07. pii: e111373. [Epub ahead of print]15
    How membranes shape up for lipid transfer.
    Takashi Hirashima, Toshiya Endo.
      The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.
    Keywords:  biochemistry; cardiolipin; chemical biology; lipid transport; mitochondria; none; phosphatidic acid
    DOI:  https://doi.org/10.7554/eLife.111373
  10. bioRxiv. 2026 Apr 24. pii: 2026.04.22.720193. [Epub ahead of print]
    Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
    Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.
      The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans . Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
    DOI:  https://doi.org/10.64898/2026.04.22.720193
  11. Redox Biol. 2026 Apr 30. pii: S2213-2317(26)00193-X. [Epub ahead of print]94 104195
    Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.
    Lianne Jhc Jacobs, Sebastian Doll, Dietrich Trümbach, Matteo Veronese, Giada Di Pietro, Fatma Isil Yapici, Lidwina Hasberg, Pascal Gentzsch, Sarah Gerlich, Jens Hansen, Silvia von Karstedt, Elena I Rugarli, Marcus Conrad, Armindo Salvador, Jan Riemer.
      Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.
    DOI:  https://doi.org/10.1016/j.redox.2026.104195
  12. Front Neurol. 2026 ;17 1775667
    Commentary: Profiles of paediatric patients experiencing stroke-like episodes associated with mitochondrial disease.
    Josef Finsterer.
      
    Keywords:  L-arginine; MELAS; mitochondrial disorder; seizure; stroke-like episode
    DOI:  https://doi.org/10.3389/fneur.2026.1775667
  13. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
  14. Mol Cell Biochem. 2026 May 02.
    Polarized mitochondrial respiratory chain complexes in synaptic mitochondria induced by plasticity signals.
    Xi Wang, Gang Zhou, Yi Hu, Kaiyuan Liu, Chong Zuo, Tingting Yan, Ji-Song Guan, Hong Xie.
      Mitochondria are well established as key supporters of synaptic plasticity, yet the nanoscale spatial distribution of specific mitochondrial membrane proteins during this process remains poorly understood. Using 3D MINFLUX nanoscopy, we investigated their polarized distribution within synapses of cortical neurons undergoing chemical long-term potentiation (cLTP). Upon cLTP induction in DIV17 neurons, we observed an increased mitochondrial occupancy in stimulated synapses. Respiratory complexes of the inner mitochondrial membrane (IMM)-such as COX-IV and SDHA-showed a polarized accumulation near presynaptic sites, as validated by cluster analysis and 3D mapping. By contrast, outer mitochondrial membrane (OMM) proteins, including TOMM20 and VDAC, exhibited no significant polarized distribution. Together, these results demonstrate that cLTP selectively remodels the inner mitochondrial membrane to address localized energy requirements, highlighting the power of 3D MINFLUX for resolving protein organization with subcellular precision.
    Keywords:  3D MINFLUX nanoscopy; Chemical long-term potentiation; Mitochondria; Respiratory chain complex; Synaptic plasticity
    DOI:  https://doi.org/10.1007/s11010-026-05562-6
  15. Int J Mol Sci. 2026 Apr 14. pii: 3499. [Epub ahead of print]27(8):
    Synphilin-1 Is Essential for Cytoskeletal Integrity of Brain Ventricular Cilia and Mitochondrial Proteostasis.
    Malik Farhoud, Ankit Kumar Shah, Nicole Pavoncello, Haya Hamza, Fatimah Abd Elghani, Vered Shani, Michal Toren-Hershkoviz, Sofia Zaer, Galit Saar, Lihi Shaulov, Zagorka Vitic, Claude Brodski, Inon Maoz, Salman Zubedat, Avi Avital, Hazem Safory, Simone Engelender.
      Parkinson's disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology.
    Keywords:  Parkinson’s disease; cilia; hydrocephalus; microtubules; neurodegeneration; synphilin-1
    DOI:  https://doi.org/10.3390/ijms27083499
  16. Cancer Discov. 2026 May 05. OF1
    Proteasome-Heme Axis Links Mitochondrial Stress to T-Cell Exhaustion.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-043
  17. Front Mol Neurosci. 2026 ;19 1786336
    LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif.
    Md Shariful Islam, Valentin Cóppola-Segovia, Alessandra Musso, Darren J Moore.
       Introduction: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing a Roc GTPase domain and a serine/threonine-directed protein kinase domain, with PD-linked mutations known to enhance LRRK2 kinase activity and neuronal toxicity. Our previous studies identified the Golgi protein, ADP-Ribosylation Factor GTPase-Activating Protein 1 (ArfGAP1), as a novel modifier of LRRK2-induced cellular toxicity, where it can serve as a GAP-like protein and a robust kinase substrate of LRRK2.
    Methods: Here, we further explore the phosphorylation of ArfGAP1 by LRRK2 and its functional consequences.
    Results: LRRK2 mediates the robust phosphorylation of ArfGAP1 in vitro within its lipid-sensing ALPS2 motif at residues Ser284, Thr291, and Thr292. We mutated these three candidate phosphorylation sites, either alone or combined, to create hydrophobic phospho-null or charged phospho-mimicking versions of ArfGAP1. We find that modulating ArfGAP1 phosphorylation at these sites impairs its normal capacity to induce Golgi fragmentation upon overexpression in neural cells. Blocking phosphorylation impairs ArfGAP1-induced neurite outgrowth inhibition in primary neurons and protects against the pathogenic effects of PD-linked G2019S LRRK2. ArfGAP1 interactome analysis in neural cells identifies 114 putative interacting proteins with a proportion of these localized to mitochondria, including the outer membrane proteins Voltage-Dependent Anion Channel (VDAC) 1-3. An ArfGAP1 triple phospho-mimic mutant displays an increased interaction with mitochondrial VDACs owing to the redistribution of ArfGAP1 from the cis-Golgi to the cytoplasm. Mimicking ArfGAP1 phosphorylation also blocks the formation of Golgi-derived vesicles following mild ER stress.
    Discussion: Our data provides evidence for a complex functional interaction between LRRK2 and ArfGAP1 that serves to regulate ArfGAP1 subcellular localization, protein interactions, activity and neuronal integrity via LRRK2-mediated phosphorylation of its membrane-binding ALPS2 motif. Our findings support additional validation of ArfGAP1 as a putative therapeutic target for modulating LRRK2-linked PD.
    Keywords:  ArfGAP1; Golgi; LRRK2; mitochondria; phosphorylation
    DOI:  https://doi.org/10.3389/fnmol.2026.1786336
  18. bioRxiv. 2026 Apr 25. pii: 2026.04.24.719390. [Epub ahead of print]
    Phosphorylated ubiquitin is a secondary messenger and an epigenetic mark mediating mitochondria to nucleus signaling.
    Thomas J Mercer, Bence Daniel, Craig Fredrickson, Daniel Le, Serena Lee, Vineet Vinay Kulkarni, Xu Hou, Fabienne C Fiesel, Hai Ngu, Min Jung, Brent J Ryan, Rachel Heon-Roberts, Amelia J Smith, Vasumathi Kameswaran, Tommy K Cheung, Denise Gastaldo, Dennis W Dickson, Wolfdieter Springer, Claire Jeong, Oded Foreman, Christopher M Rose, Baris Bingol.
      Parkinson's disease (PD) is commonly associated with dysfunctional mitochondrial homeostasis. PINK1, a S/T kinase mutated in early-onset PD, generates phosphoserine 65 ubiquitin (pS65Ub) on damaged mitochondria facilitating their removal. Here, we show that pS65Ub translocates into the nucleus after generation at damaged mitochondria and is directly attached to substrates by resident E3 ligases. Histone H2A is a major substrate and is modified at lysine 119 (H2AK119) by the polycomb silencer, E3 ligase RING1B. At nucleosomes, pS65Ub simultaneously suppresses RING1B and potentiates H2A deubiquitinases USP16 and USP21. Epigenetic profiling and RNA sequencing reveal that pS65Ub is enriched at the promoters of poorly expressed yet dynamically regulated genes and is associated with H2AK119ub depletion. Functionally, we show that pS65Ub enrichment drives polycomb target gene expression, which accelerates the maturation of dopaminergic neurons. Importantly, post-mortem PD brains exhibit elevated nuclear pS65Ub, potentially linking nuclear pS65Ub accumulation with disease pathogenesis. Together, these data indicate that pS65Ub generated at damaged mitochondria regulates fundamental cellular processes at distant sites.
    DOI:  https://doi.org/10.64898/2026.04.24.719390
  19. EMBO Rep. 2026 May 02.
    STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture.
    Ruiyang Guo, Yabo Guo, Runguo Shu, Jiajia Qian, Jiawei Wang, Ruobing Li, Ti Qin, Ziyi Wang, Hongtao Tian, Mengchen Wu, Long Zhou, Xiaogang Guo, Shan Zhang.
      Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5'UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the SLC35A4 transcript, we show that its 5'UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (SLC35A4 stress response regulating MICOS interactor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of SLC35A4-a Golgi nucleotide sugar transporter-upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of "gene symbiosis" that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.
    DOI:  https://doi.org/10.1038/s44319-026-00783-8
  20. Front Cardiovasc Med. 2026 ;13 1802202
    Case Report: A young man with mitochondrial disease: intellectual impairment and myocardial hypertrophy.
    Xiao Luo, Ling Li, Gaofeng Su.
      Mitochondrial diseases are rare multisystem disorders caused by pathogenic variants in mitochondrial or nuclear DNA. We report a 23-year-old male presenting with exercise intolerance, fatigue, sluggish responsiveness, and a history of ptosis and bilateral hearing loss. Echocardiography revealed left ventricular hypertrophy, while brain MRI showed cerebellar atrophy and ventricular enlargement. Laboratory tests demonstrated elevated serum lactate, HbA1c, and high-sensitivity cardiac troponin T. Targeted sequencing identified a pathogenic m.3243A > G variant in the MT-TL1 gene with 55.6% heteroplasmy, confirming mitochondrial encephalomyopathy with cardiac involvement. This case highlights the phenotypic heterogeneity and diagnostic challenges of m.3243A > G-related disorders.
    Keywords:  MT-TL1 gene; cardiomyopathy; m.3243A > G variant; mitochondrial cardiomyopathy; mitochondrial diseases
    DOI:  https://doi.org/10.3389/fcvm.2026.1802202
  21. Cell Metab. 2026 May 05. pii: S1550-4131(26)00143-9. [Epub ahead of print]38(5): 838-840
    Special packaging enables effective mitochondrial delivery.
    Caleb Jerred, Judith Hatzfeld, Alessandro Prigione.
      Mitochondrial transplantation has emerged as a promising, though still experimental, strategy for treating mitochondria-related diseases. In a recent study in Cell, Du et al. demonstrate that packaging mitochondria within erythrocyte-derived plasma membranes enhances delivery efficiency and integration, thereby advancing the translational potential of this approach toward clinical application.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.005
  22. J Cell Biol. 2026 Jul 06. pii: e202411196. [Epub ahead of print]225(7):
    Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
    Christian Covill-Cooke, Takashi Hirashima, Shin Kawano, Joe Ganellin, Andrew Moody, Sabine N S van Schie, Arun T John Peter, Chika Horie Saito, Toshiya Endo, Benoît Kornmann.
      Yeast mitochondria receive the majority of their lipids from the ER via the heterotetrameric ERMES lipid transport complex. This complex is thought to establish a lipid-transporting bridge of fixed composition spanning the space between both organelles. Intriguingly, however, some of the lipid-transporting components of the complex can be replaced by an artificial ER-mitochondria tether without lipid transport activity, questioning ERMES' relevance in lipid transport. Here, we show that Mmm1, one of the four ERMES subunits, alone is sufficient to support ERMES function when it is artificially tethered to mitochondria, provided its lipid-binding domain is intact. Combined with our previous finding that the absence of Mdm12 and Mdm34 can be rescued by the presence of Mmm1 and the artificial tethering protein ChiMERA, our results suggest that Mmm1 can act as the sole lipid transporter at the ER-mitochondrial contact sites, provided that Mdm10 is present, even in the absence of the other two subunits. Thus, our work reconciles ERMES' importance in lipid transport with the fact that the lipid transport activity of some of its components is not strictly necessary for function.
    DOI:  https://doi.org/10.1083/jcb.202411196
  23. Genes (Basel). 2026 Apr 17. pii: 472. [Epub ahead of print]17(4):
    Enrichment of Rare Variants in Nuclear-Encoded Mitochondrial Metabolism Genes in Patients with Early-Onset or Familial Parkinson's Disease.
    Gaber Bergant, Vesna M van Midden, Polina Tsygankova, Dorian Laslo, Valentino Rački, Dejan Georgiev, Eliša Papić, Marija Branković, Milena Janković, Marina Svetel, Nataša Teran, Natasa Dragasević Misković, Igor Petrović, Aleš Maver, Ivana Novaković, Zvezdan Pirtošek, Martin Rakuša, Vladimira Vuletić, Borut Peterlin.
      Introduction: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, with several proposed pathogenic mechanisms. Given the established role of mitochondrial dysfunction in PD, this study seeks to investigate the enrichment of rare genetic variants tied to mitochondrial metabolism in cases of early-onset and familial PD. Methods: We performed a retrospective analysis on 248 early-onset and familial PD patients and 1622 control individuals. We assessed both pathway-level and gene-level burden of germline rare variants detected using exome sequencing in 467 nuclear genes related to mitochondrial metabolism. Results: Gene-set mutation burden analysis indicated an increased burden in genes associated with mtDNA maintenance. In addition, gene-level analysis identified a possible association between PD and rare variant burden in 14 mitochondrial metabolism-related genes under dominant or recessive inheritance models. Conclusions: Our findings support a potential contribution of rare germline variants affecting mitochondrial metabolism to the susceptibility in early-onset and familial PD.
    Keywords:  Parkinson’s disease; mitochondrial metabolism; mitochondrial variants; mutation burden analysis
    DOI:  https://doi.org/10.3390/genes17040472
  24. Nat Metab. 2026 May 08.
    Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control.
    Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.
      Metformin is a versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying its clinical effects, including attenuated postprandial glucose excursions and elevated intestinal glucose uptake, remain unclear. Here we map these and other effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving the uptake of excess glucose and its conversion to lactate and lactoyl-phenylalanine. We also find that glucose lowering by metformin is due to repeated bolus exposure rather than a cumulative chronic response. Notably, the efficacy of phenformin, another biguanide, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.
    DOI:  https://doi.org/10.1038/s42255-026-01530-y
  25. Mol Cell. 2026 May 07. pii: S1097-2765(26)00244-3. [Epub ahead of print]86(9): 1595-1597
    Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate.
    Edrees H Rashan, Sophie D'Halleweyn, Matthew G Vander Heiden.
      In a recent issue of Cell, Xie et al.1 report that an important function of mitochondrial aconitase is to limit toxic citrate accumulation, suggesting a role for the canonical TCA cycle in physiology beyond ATP production and precursor biosynthesis.
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.010
  26. bioRxiv. 2026 Apr 28. pii: 2026.04.27.718938. [Epub ahead of print]
    Lactylation landscape of mitochondrial proteins in myocardial infarction.
    Ashlesha Kadam, Shiridhar Kashyap, Kunal Samantaray, Natasha Jaiswal, Shanikumar Goyani, Philip A Kramer, Pourhadi Hadi, Jingyun Lee, Cristina M Furdui, Pooja Jadiya, Dhanendra Tomar.
      Metabolic reprogramming is a hallmark of myocardial infarction (MI), in which cardiomyocytes shift from fatty acid oxidation to anaerobic glycolysis, leading to elevated lactate production and mitochondrial dysfunction. Lactylation, a recently described lysine post-translational modification, has emerged as a metabolic signaling mechanism; however, its role within mitochondria during MI remains poorly understood. Here, we define the mitochondrial lactylome following MI and examine how modulation of lactate transport influences mitochondrial metabolism and redox homeostasis. Using quantitative proteomics, we identify extensive remodeling of mitochondrial protein lactylation after MI, affecting enzymes involved in bioenergetics, redox regulation, and metabolic control. Pharmacological inhibition of monocarboxylate transporter-1 (MCT1) using AZD3965 further reshapes the mitochondrial lactylome, increasing lactylation of specific metabolic and redox-associated proteins without uniformly exacerbating mitochondrial dysfunction. Despite sustained impairment of global cardiac function, MCT1 inhibition attenuates post-MI fibrosis and inflammation and partially restores mitochondrial respiratory capacity. Consistent with in vivo findings, genetic or pharmacological inhibition of MCT1 in hypoxic cardiomyocytes-derived cells reduces mitochondrial reactive oxygen species, decreases inhibitory pyruvate dehydrogenase phosphorylation, and improves mitochondrial bioenergetics. Together, these findings reveal that mitochondrial lactylation is a context-dependent regulator of mitochondrial metabolism and redox balance following MI. Rather than acting solely as a pathological modification, lactylation integrates lactate availability with mitochondrial function to influence inflammatory and fibrotic remodeling, highlighting mitochondrial metabolic plasticity as a potential therapeutic target in ischemic heart disease.
    Highlights: Myocardial infarction (MI) increases mitochondrial protein lactylation, with 361 identified lactylated proteins.AZD3965-mediated MCT1 inhibition further elevates mitochondrial lactylation.Distinct alterations in mitochondrial proteins and pathways (TCA cycle, amino acid metabolism, gene expression) were observed.AZD3965 reduces cardiac fibrosis and inflammation and partly improves mitochondrial respiration post-MI, but cardiac function remains impaired.
    DOI:  https://doi.org/10.64898/2026.04.27.718938
  27. BMJ Case Rep. 2026 May 04. pii: e272561. [Epub ahead of print]19(5):
    β-ureidopropionase deficiency mimicking Leigh syndrome associated with methylmalonic aciduria.
    Giulia Ferrera, Sara Boenzi, Eleonora Lamantea, Daniele Ghezzi, Anna Ardissone.
      β-ureidopropionase (βUP) deficiency, caused by pathogenic variants in UPB1, is a rare autosomal recessive disorder with fewer than 60 reported cases to date. Clinical presentation is highly variable, ranging from asymptomatic individuals to severe neurodevelopmental disorders. Diagnosis relies on the detection of pyrimidine degradation metabolites, such as N-carbamyl-β-alanine (NCβA) and N-carbamyl-β-aminoisobutyrate (NCβAIBA), which are not widely available in routine clinical practice.We report a 7-year-old boy with early-onset developmental delay and regression, Leigh-like basal ganglia lesions on brain MRI, and persistent elevation of urinary methylmalonic acid (MMA). Muscle biopsy revealed an isolated respiratory chain complex I deficiency. Genetic testing identified two novel biallelic UPB1 variants, and urinary analysis confirmed marked elevation of pyrimidine degradation metabolites, establishing the diagnosis of βUP deficiency.This case expands the clinical and neuroradiological spectrum of βUP deficiency and identifies elevated urinary MMA as a previously unreported finding in this disorder. Given the widespread availability of urinary organic acid analysis, MMA may represent a possibly useful and accessible biomarker to support diagnosis. βUP deficiency should be considered in the differential diagnosis of children with Leigh-like encephalopathy and unexplained MMA elevation.
    Keywords:  Clinical neurophysiology; Neuro genetics
    DOI:  https://doi.org/10.1136/bcr-2026-272561
  28. Nat Commun. 2026 05 07. pii: 4195. [Epub ahead of print]17(1):
    Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
    Maria E Gierisch, Enrica Barchi, Mirco Marogna, Moritz H Wallnöfer, Maria Ankarcrona, Luana Naia, Florian A Salomons, Nico P Dantuma.
      The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we conduct a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter. Genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, are enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A leads to dissociation of the aggregation-prone substrate from mitochondria, which is accompanied by enhanced ubiquitin-dependent proteasomal degradation. The presence of an aggregation-prone, amphipathic helix that localizes the reporter to mitochondria is crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhances degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose that mitochondria serve as a holdout compartment for aggregation-prone proteins. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72783-0
  29. Stem Cell Res. 2026 Apr 28. pii: S1873-5061(26)00098-X. [Epub ahead of print]94 104002
    Generation of an iPSC line IUFi004-A-13 with homozygous NDUFS1 mutation for the study of Leigh syndrome.
    Caleb Jerred, Haribaskar Ramachandran, Barbara Hildebrandt, Annika Zink, Natascia Ventura, Andrea Rossi, Alessandro Prigione.
      NDUFS1 is a critical component of mitochondrial respiratory chain Complex I (CI). Pathogenic variants of NDUFS1 can cause Leigh syndrome (LS), a severe pediatric mitochondrial disorder. To model NDUFS1-linked LS, we generated an iPSC line with homozygous missense mutations in exon 8 using CRISPR/Cas9. The cell line demonstrated typical morphology, expression of iPSC markers, ability to differentiate into all three germ layers, and genomic integrity. This model will enable the study of LS caused by CI in an isogenic context.
    DOI:  https://doi.org/10.1016/j.scr.2026.104002
  30. Case Rep Ophthalmol. 2026 Jan-Dec;17(1):17(1): 387-395
    Two Novel Variants in MT-RNR1 Gene Associated with Hereditary Optic Neuropathy: A Case Report.
    Sara KamaliZonouzi, Jonathan Micieli.
       Introduction: Hereditary optic neuropathies are primarily disorders of mitochondrial dysfunction leading to the metabolic failure of the highly energy-dependent retinal ganglion cells. Beyond the canonical variants found in OPA1 or the mitochondrial genome, a growing subset of patients exhibits progressive optic atrophy of unknown origin. Identifying these variants is critical, as they might lead to a diagnostic delay. We report 2 cases with previously unreported MT-RNR1 variants, potentially contributing to a hereditary optic neuropathy.
    Case Presentations: A 55-year-old woman with painless progressive optic neuropathy presented with bilateral central scotomas and temporal optic disc pallor. Nutritional, inflammatory, and demyelinating causes were excluded. Genetic testing revealed MT-RNR1:m.1019A>G variant, potentially contributing to a hereditary optic neuropathy. A 59-year-old woman with similar bilateral temporal pallor and symmetric retinal nerve fiber layer thinning was found to harbor MT-RNR1:m.1183T>C variant.
    Conclusion: MT-RNR1 gene variant was the possible cause of vision loss in these patients with mild vision loss and a clinical picture consistent with a hereditary optic neuropathy. Herein, we describe two novel variants and associated clinical features. This case report introduces a previously unrecognized genetic variant, potentially contributing to a hereditary optic neuropathy.
    Keywords:  Hereditary optic neuropathy; MT-RNR1; m.1019A>G; m.1183T>C
    DOI:  https://doi.org/10.1159/000551049
  31. J Physiol. 2026 May 07.
    Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
    Márcio Augusto Campos-Ribeiro, Rudá Prestes E Albuquerque, Thiago N Menezes, Vanessa Morais Lima.
      
    Keywords:  cytoskeleton; mitochondrial dynamics; mitochondrial function; skeletal muscle metabolism
    DOI:  https://doi.org/10.1113/JP291379
  32. bioRxiv. 2026 Apr 20. pii: 2026.04.20.719537. [Epub ahead of print]
    MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling.
    Anastasia Rumyantseva, Alissa Wilhalm, William Carter, Trevor S Tippetts, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart undergoes a rapid metabolic transition from fetal glycolysis to oxidative phosphorylation, requiring coordinated metabolic remodeling. Mechanisms driving this transition remain unclear. Here, we demonstrate that sufficient mitochondrial S-adenosylmethionine (mitoSAM), imported via the solute carrier Slc25a26 , is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.
    DOI:  https://doi.org/10.64898/2026.04.20.719537
  33. Expert Opin Ther Targets. 2026 May 08.
    Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
    Marcel V Alavi.
       INTRODUCTION: Autosomal Dominant Optic Atrophy (ADOA) is a rare hereditary optic neuropathy primarily caused by OPA1 mutations. Retinal ganglion cell (RGC) loss results in variable visual impairments, occasionally accompanied by extra-ocular manifestations. ADOA also involves a developmental component consistent with OPA1's essential role in mitochondrial fusion, cristae organization, and quality control. As such, ADOA serves as a paradigm for studying mitochondrial contributions to neurodegeneration.
    AREAS COVERED: This article provides a comprehensive overview of ADOA, covering genetic and clinical aspects while distinguishing between degenerative and developmental features of the pathology. The author examines OPA1 function and assesses emerging therapeutic strategies - ranging from gene augmentation and small-molecule therapeutics to alternative targets - before appraising translational challenges.
    EXPERT OPINION: Antisense therapies targeting OPA1 haploinsufficiency are among the more advanced ADOA treatments currently under human safety evaluation, with other modalities following closely in development. However, the field still lacks robust clinical endpoints for the highly variable and slowly progressive phenotype. Furthermore, developmental RGC loss may limit therapeutic efficacy of late-stage interventions - a challenge compounded by the difficulty of early diagnosis. Nevertheless, the FDA's recent shift toward Bayesian statistical frameworks and the emergence of neuroprotective alternative targets are expected to streamline the clinical development for ADOA.
    Keywords:  Antisense oligonucleotides; Haploinsufficiency; OMA1; OPA1; autosomal dominant optic atrophy (ADOA); gene therapies; mitochondrial dynamics; neuroprotection; retinal ganglion cells (RGCs); small molecules
    DOI:  https://doi.org/10.1080/14728222.2026.2671678
  34. Cell Commun Signal. 2026 May 02.
    Cryptic DNA sequences encode a temperature sensor to regulate mitochondrial suicide during neuronal differentiation.
    Filip Vujovic, Mary Simonian, Lake-Ee Quek, Kang-Yu Peng, Neil Hunter, Ramin M Farahani.
      Accumulating evidence suggests that transient mitochondrial hyperactivity shapes the early stage of neuronal differentiation although mechanistic details remain largely unknown. Here, we report a mitochondrial suicide program which is activated in response to thermal flux to terminate this early stage of mitochondrial hyperactivity. A conserved stem loop at the mitochondrial origin of replication of the light strand operates as a thermal sensor, denaturing upon enhanced thermal flux and repressing the replication of the parental heavy strand of mitochondrial DNA. This triggers a quasi-replication of mitochondrial DNA characterised by replication of only the parental light strand. The non-replicated single-stranded heavy strand is then released and operates as a natural antisense DNA which sequesters complementary mRNAs encoded by the heavy strand. Subsequent degradation of the bound mRNAs by RNase H1 completes the cycle by triggering mitochondrial transcriptional decline and ultimately mitochondrial death.
    Keywords:  Mitochondrial replication; RNase H1; Single-stranded DNA; Thermal flux
    DOI:  https://doi.org/10.1186/s12964-026-02914-z
  35. bioRxiv. 2026 Apr 21. pii: 2026.04.16.718990. [Epub ahead of print]
    NMNAT2-SARM1 Axis Drives Redox Failure and Disrupts APP Processing in Neurons.
    Andrea Enriquez, Sen Yang, Karen Ling, Paymaan Jafar-Nejad, Hui-Chen Lu.
      Metabolic dysfunction and proteinopathy are hallmarks of many neurodegenerative diseases, yet their mechanistic interplay remains poorly understood. Here, we demonstrate that amyloid precursor protein (APP) processing in cortical neurons is disrupted upon loss of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), the NAD⁺-synthesizing enzyme in neurons, resulting in accumulation of APP C-terminal fragments (APP-CTFs). Knockdown (KD) of the NAD⁺ hydrolase sterile alpha and TIR motif-containing protein 1 (SARM1) restores APP-CTF levels in NMNAT2 knockout (KO) neurons to wild-type levels, whereas NAD⁺ supplementation yields modest rescue. Redox profiling indicates that NMNAT2 loss reduces NAD⁺/NADH redox potential when APP-CTF starts accumulating. Seahorse metabolic flux analysis shows that NMNAT2 deficiency induces early glycolytic impairment, followed by deficits in mitochondrial respiration. Notably, SARM1 KD, but not NAD⁺ supplementation, rescues mitochondrial function in NMNAT2 KO neurons. Temporal profiling of NMNAT2 KO neurons revealed a biphasic pattern in APP-CTF accumulation, with an initial gradual increase followed by a marked acceleration, paralleling the transition from an initially small number to a substantially greater number of differentially expressed proteins. Pathway enrichment analysis of proteomic changes suggests JNK/MAPK signaling is upregulated in the early phase, with late-phase downregulation of mitochondrial function and upregulation of endoplasmic reticulum stress and unfolded protein response pathways. Collectively, these findings demonstrate that neuronal NAD⁺ depletion drives a progressive, SARM1-dependent disruption of redox homeostasis and proteostasis, resulting in impaired APP processing. The NMNAT2-SARM1 axis emerges as a critical pathway linking metabolic stress to proteinopathy, positioning SARM1 as a key mediator of neurodegenerative dysfunction.
    DOI:  https://doi.org/10.64898/2026.04.16.718990
  36. Redox Biol. 2026 Apr 24. pii: S2213-2317(26)00189-8. [Epub ahead of print]93 104191
    An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.
    Yidan Sun, June-Chiew Han, Kenneth Tran, Toan Pham, Qiang Zhou, Jun Lu.
      As the global population ages rapidly, delaying and preventing age-related diseases have become urgent priorities in public health and biomedical research. During aging, mitochondrial dysfunction is a core molecular hallmark and a common pathogenic mechanism underlying multiple age-related disorders. Age-related mitochondrial dysfunction typically manifests as diminished metabolic capacity, impaired organelle renewal, and disrupted redox homeostasis. These factors interact to form a feedback loop constraining mitochondrial adaptability. Specifically, the interdependent decline in NAD+ availability, impaired mitochondrial biogenesis, and excessive oxidative stress render single-pathway interventions ineffective in mitigating systemic functional impairments triggered by aging. To address this complex mechanism, this review presents a novel tri-axis anti-aging model encompassing three key compounds: nicotinamide mononucleotide/nicotinamide riboside (NMN/NR), pyrroloquinoline quinone (PQQ), and l-ergothioneine (EGT). Within this framework, NMN/NR serves as a broad NAD+-dependent regulator of mitochondrial homeostasis, with its most immediate effects on metabolic activation, while PQQ and EGT may further strengthen mitochondrial remodeling and redox resilience, respectively. While each compound has distinct functional emphases, they are highly mechanistically coupled, collectively forming a closed-loop network regulating mitochondrial number, function, and homeostasis. This review synthesizes preclinical and emerging clinical evidence supporting the standalone or combined use of NMN/NR, PQQ, and EGT across various diseases. Collectively, by conceptualizing mitochondrial aging as a systemic imbalance rather than isolated molecular defects, this paper highlights a three-axis model of NMN/NR, PQQ, and EGT. This framework offers a theoretical foundation for mitochondrial-targeted anti-aging interventions while laying the groundwork for future clinical research, nutritional interventions, and the development of multi-target combination strategies.
    Keywords:  Anti-aging; Ergothioneine; Mitochondria; NMN; NR; PQQ
    DOI:  https://doi.org/10.1016/j.redox.2026.104191
  37. Reprod Sci. 2026 May 04.
    Mitochondrial Function and Dysfunction in Female Fertility: Biological Mechanisms, Genetic Determinants, and Therapeutic Opportunities - A Review.
    Sahana Nagaraju, Syed Sagheer Ahmed, Bharathi Doddlu Raghunathnaidu, Mohammad Ali.
      Female fertility relies on tightly regulated mitochondrial bioenergetics to support oocyte maturation, fertilization, and early embryonic development. Beyond ATP generation, mitochondria orchestrate redox signaling, calcium homeostasis, metabolic-epigenetic coupling, and nuclear-mitochondrial communication, thereby shaping oocyte competence and ovarian longevity. Aging, obesity, metabolic stress, and genetic perturbations disrupt these regulatory networks, leading to redox imbalance, impaired oxidative phosphorylation, altered mitochondrial dynamics, and mitochondrial DNA instability. These changes compromise granulosa cell support, impair meiotic progression, and accelerate ovarian aging, contributing to female infertility disorders such as polycystic ovary syndrome. This review integrates therapeutic strategies that actively reprogram ovarian mitochondrial function rather than merely counteracting damage. Mitochondria-targeted antioxidants-including melatonin, resveratrol, N-acetylcysteine, mitochondria-directed scavengers, and coenzyme Q10 restore redox balance, stabilize mitochondrial dynamics, and enhance oocyte bioenergetics. In parallel, metabolic modulators such as metformin, dapagliflozin, and glucagon-like peptide-1 receptor agonists reprogram ovarian bioenergetics by reshaping substrate utilization, suppressing inflammatory and oxidative signaling, and improving mitochondrial efficiency within the ovary. Collectively, these interventions demonstrate that, positioning mitochondria-centered therapies as promising strategies to preserve fertility and extend the female reproductive health span.
    Keywords:  Female fertility; Mitochondria-targeted therapeutics; Mitochondrial dysfunction; Ovarian aging; mtDNA instability
    DOI:  https://doi.org/10.1007/s43032-026-02113-8
  38. Acta Neuropathol Commun. 2026 May 05.
    Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.
    Anna Maria Haschke, Anja von Renesse, Eugenio Graceffo, Susanne Morales-Gonzalez, Alessandro Prigione, Christoph Hübner, Werner Stenzel, Markus Schuelke.
      During muscle contraction, increased influx of calcium from the myocyte cytosol into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) links calcium homeostasis with high ATP provision. The MCU is located at the inner mitochondrial membrane and one of its structural components, the mitochondrial calcium uniporter regulator 1 (MCUR1), promotes its activity. Although MCUR1 function has been studied in cell models, mutations have not yet been associated with human disease. Here, we present a patient with proximal muscle weakness and atrophy, showing histological features of autophagic vacuoles with sarcolemmal features, who carries a homozygous MCUR1 nonsense mutation. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mtCa²⁺ uptake, that had been stimulated both by histamine or rising extracellular calcium exposure. Autophagic flux and histologic markers for autophagy (LAMP2, LCB3) were increased in the patient. However, the MCUR1 mutation did not alter MCU-complex assembly or its subcellular location, nor the resting mitochondrial membrane potential. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mtCa2+ uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans.
    Keywords:  Autophagic vacuoles; Calcium transport; Mitochondrial calcium uniporter; Mitochondrium; Vacuolar myopathy
    DOI:  https://doi.org/10.1186/s40478-026-02313-y
  39. Mol Cell Proteomics. 2026 May 06. pii: S1535-9476(26)00078-2. [Epub ahead of print] 101582
    Dynamic proximity networks of myosin-19 (Myo19) and its mitochondrial receptors Miro2 and metaxin-3.
    Aya Attia, Jürgen Eirich, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Iris Finkemeier, Martin Bähler.
      Myosin-19 (Myo19) plays a crucial role in mitochondrial dynamics, cristae organization and ER-mitochondria contact sites (ERMCS). It regulates cytokinesis and inheritance of mitochondria to daughter cells. To better understand the dynamic molecular network of Myo19 during the cell cycle, we determined the in vivo proximity protein interaction networks of Myo19 in interphase and prometaphase using proximity-based TurboID biotinylation followed by mass spectrometry. We further determined the proximity networks of its known mitochondrial binding partners Miro2 and metaxin-3. The outer mitochondrial membrane protein Miro2 not only binds but also stabilizes Myo19. This interaction depends on the nucleotide state of the N-terminal GTPase domain of Miro2. Therefore, we analysed both the proximity networks of Miro2 and its GTP-binding mutant Miro2 T18N. We were able to show a differential association of Myo19 during the cell cycle with functional protein clusters and a participation of Myo19 in mitochondrial trafficking, ERMCS and mitochondria intermembrane space bridging complex / cristae organizing system (MIB/MICOS). The proximity network of Myo19 showed more overlap with Miro2 than metaxin-3. Abolishing GTP-binding to the N-terminal GTPase domain of Miro2 reduced the number of proteins in proximity of Miro2 considerably. In conclusion, we discovered a comprehensive dynamic in vivo protein proximity network of Myo19 and its mitochondrial receptors Miro2 and metaxin-3.
    Keywords:  ERMCS; MIB/MICOS; MTX3; Miro2; Mitochondrial dynamics; Myo19; OMM; TurboID Proximity Labelling; actin; mitochondria; myosin
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101582
  40. Elife. 2026 May 05. pii: RP106587. [Epub ahead of print]14
    Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics.
    David Papadopoli, Ranveer Palia, Predrag Jovanovic, Sébastien Tabariès, Emma Ciccolini, Valerie Sabourin, Sebastian Igelmann, Shannon McLaughlan, Lesley Zhan, HaEun Kim, Nabila Chekkal, Krzysztof J Szkop, Thierry Bertomeu, Jibin Zeng, Julia Vassalakis, Farzaneh Afzali, Slim Mzoughi, Ernesto Guccione, Mike Tyers, Daina Avizonis, Ola Larsson, Lynne-Marie Postovit, Sergej Djuranovic, Josie Ursini-Siegel, Peter M Siegel, Michael Pollak, Ivan Topisirovic.
      Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.
    Keywords:  cancer biology; cell biology; human; mRNA translation; metabolism; mouse; signal transduction
    DOI:  https://doi.org/10.7554/eLife.106587
  41. Front Physiol. 2026 ;17 1782998
    Investigation of mitochondrial inner membrane ion conductance by planar lipid bilayer electrophysiology.
    Amrendra Kumar, Eleanora Margulis, Nelli Mnatsakanyan.
      Mitochondrial ion channels are proteins of the inner and outer mitochondrial membranes that regulate ion flux and control various cellular processes, including calcium signaling, bioenergetic and metabolic functions, and cell death. Their precise regulation is essential to maintaining normal mitochondrial function and preventing pathological processes. Patch-clamp and planar lipid bilayer electrophysiology techniques have been used to measure ion flow directly across the membrane, thereby revealing the gating kinetics and pharmacological profile of ion channels in real time. Here, we describe a planar lipid bilayer electrophysiology approach for assessing mitochondrial ion channel conductance using mitochondrial inner membrane vesicles (IMVs). The comparative electrophysiology analysis between IMVs and purified mitochondrial proteins, ATP synthase, and the adenine nucleotide translocator (ANT), demonstrates that planar lipid bilayer electrophysiology is a robust tool for biophysical characterization of mitochondrial ion channels using IMVs. This approach is particularly valuable for investigating ion channel properties under controlled yet physiologically relevant conditions and for evaluating the direct modulatory effects of different pharmacological agents.
    Keywords:  ATP synthase leak channel; adenine nucleotide translocator (ANT); mitochondria; patch-clamp; planar lipid bilayer electrophysiology
    DOI:  https://doi.org/10.3389/fphys.2026.1782998
  42. Bioinformatics. 2026 May 04. pii: btag255. [Epub ahead of print]
    AXOLOTL: an accurate method for detecting aberrant gene expression in rare diseases using coexpression constraints.
    Wenjian Xu, Yansheng Shen, Xiangfu Liu, Fei Leng, Yang Liu.
       MOTIVATION: The assessment of aberrant transcription events in rare disease patients holds great promise for enhancing the prioritization of causative genes-a strategy already widely adopted in clinical settings to improve diagnostic accuracy. Nevertheless, the accurate identification of causal genes remains a substantial challenge.
    RESULTS: We propose AXOLOTL, a novel ensemble method for identifying aberrant gene expression events in RNA expression matrices. AXOLOTL effectively accounts for gene correlation by incorporating coexpression constraints. We demonstrated the superior performance of AXOLOTL on representative RNA-seq datasets, including those from the GTEx healthy cohort, mitochondrial disease cohorts, and collagen VI-related dystrophy cohorts. Furthermore, we applied AXOLOTL to real-world cases of neurological disorders and demonstrated its ability to accurately identify aberrant gene expression and facilitate the prioritization of pathogenic variants.
    AVAILABILITY AND IMPLEMENTATION: AXOLOTL is freely available on GitHub (https://github.com/xuwenjian85/axolotl) and Zenodo (https://doi.org/10.5281/zenodo.17940844).
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag255
  43. Nat Struct Mol Biol. 2026 May 07.
    When membrane insertion sets the pace of mitochondrial translation.
    Michele Brischigliaro, Antoni Barrientos.
      
    DOI:  https://doi.org/10.1038/s41594-026-01799-3
  44. EMBO Mol Med. 2026 May 08.
    Loss of mitochondrial DNA helicase in retinal macroglia drives neovascular retinopathy.
    Sofiia Olander, Sinem Karaman, Fumi Suomi, Kevin Aguilar, Aleksandra Zhaivoron, Maiken Nedergaard, Lina Smeds, Jussi Tiihonen, Albert Quintana, Juan Hidalgo, Kari Alitalo, Petri Ala-Laurila, Gulayse Ince-Dunn, Anu Suomalainen.
      Retinopathy is a common symptom in mitochondrial diseases, and a leading cause of blindness in working-age individuals, often arising as a consequence of diabetes. Here, we demonstrate that postnatal loss of the replicative helicase of mitochondrial DNA in the astrocytes and Müller glia induces neovascular retinopathy. In these retinas, the macroglia show pathological reactivation, leading to hallmark features of neovascularization with blood-retina-barrier leakage, secondary microgliosis, and complement cascade activation. Similar reactivation of astrocytes in the cerebral cortex does not compromise vascular integrity, indicating tissue-specific roles of mitochondrial metabolism in macroglia for vascular homeostasis. Three secreted angiogenic factors-Fgf2, Pgf, and Lcn2-known to contribute to diabetic retinopathy, were induced. Spike recordings of the most sensitive retinal ganglion cells revealed normal rod function and intact retinal coding. These findings highlight the critical role of glial mitochondrial metabolism in neovascular retinopathy, with important implications for therapy development for mitochondrial and common forms of vision loss.
    DOI:  https://doi.org/10.1038/s44321-026-00438-0
  45. Stem Cell Reports. 2026 May 07. pii: S2213-6711(26)00109-8. [Epub ahead of print] 102898
    Human organoids: Fit for drug discovery?
    Annika Wittich, Kim Krieg, Philip Gribbon, Jakob J Metzger, Alessandro Prigione, Ole Pless.
      Organoids are self-organizing three-dimensional (3D) in vitro tissues derived from pluripotent stem cells (PSCs) that recapitulate key structural and functional features of human organs. Their multicellular architecture and physiological relevance make them promising new approach methodologies (NAMs) for disease modeling, drug discovery, and toxicity testing. However, their reliability and scalability for compound screening remain under evaluation. This review summarizes current human PSC-derived organoid screening strategies, highlighting available readouts, related machine learning methods, and their potential advantages over traditional screening models. We also discuss major challenges, including assay robustness, throughput limitations, and the need for standardized protocols. Advancing validated and scalable approaches will be essential for integrating organoids into pharmaceutical development and improving the translational success of drug candidates.
    Keywords:  assay development; drug discovery; high-throughput screening; hit validation; human pluripotent stem cells; organoids; small molecules; three-dimensional
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102898
  46. Nat Metab. 2026 May 04.
    Succinate calls a time-out on pyrimidine biosynthesis.
    Désirée Schatton, Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s42255-026-01523-x
  47. Nat Struct Mol Biol. 2026 May 07.
    Membrane insertion of mitochondrial-encoded proteins regulates ribosome decoding speed.
    Thomas Schöndorf, Valentyn Petrychenko, Ilgin Kotan, Drishan Dahal, Natalia Napieraj, Luis Daniel Cruz-Zaragoza, Cong Wang, Oliver Urbach, Tanja Gall, Sven Dennerlein, Günter Kramer, Niels Fischer, Peter Rehling.
      The human mitochondrial genome encodes 13 subunits of the oxidative phosphorylation system essential for energy metabolism to drive cellular activities. Translation of 11 mRNAs by membrane-bound ribosomes is coupled to insertion of the nascent polypeptides into the inner membrane aided by the OXA1L insertase. To this end, the mechanism of membrane insertion of nascent polypeptides and the functional link to the translation process are not sufficiently understood. Here, we applied ribosome profiling to assess translation dynamics in combination with cryo-electron microscopy analysis of a COX1 ribosome-nascent chain complex to visualize cotranslational folding of the nascent chain. We find that the membrane topology of the translation product impacts translation speed and that positioning of amphipathic helices in the ribosome vestibule induces structural changes, correlating with translation pausing events. Thus, our findings reveal a link between translation process and folding and membrane insertion of nascent polypeptides at the inner mitochondrial membrane.
    DOI:  https://doi.org/10.1038/s41594-026-01803-w
  48. Nat Metab. 2026 May 04.
    Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.
    Madeleine L Hart, David Sokolov, Serwah Danquah, Eric Zheng, Alex D Doan, Kristian Davidsen, David MacPherson, Lucas B Sullivan.
      Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.
    DOI:  https://doi.org/10.1038/s42255-026-01524-w
  49. Neuron. 2026 May 01. pii: S0896-6273(26)00268-0. [Epub ahead of print]
    Mitochondrial fission factor regulates mitochondrial Ca2+ homeostasis and neuronal activity in AgRP neurons.
    Almudena Del Río-Martín, Gagik Yeghiazaryan, Rui de Oliveira Beleza, Sinika Henschke, Marie H Solheim, Paul N Mirabella, Tamara Sotelo-Hitschfeld, Corinna A Bauder, Hong Jiang, Weiyi Chen, Paul Klemm, Lukas Steuernagel, Alain J de Solís, Philipp Hammerschmidt, Henning Fenselau, F Thomas Wunderlich, Peter Kloppenburg, Jens C Brüning.
      Mitochondria represent central regulators of neuronal function, and their network is dynamically restructured via fission and fusion. The mitochondrial fission factor (MFF) serves as an adaptor protein that recruits and organizes the core fission machinery at the outer mitochondrial membrane. Here, we investigated the role of MFF in Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) in their regulation of systemic energy homeostasis. We demonstrated that mice lacking MFF in AgRP neurons exhibited increased mitochondrial size, both in AgRP neuron somata and their axonal compartments. This translated into increased mitochondrial Ca2+ uptake capacity, increased mitochondrial membrane potential, and a shift toward a more reduced mitochondrial NAD(P)H redox state. Ultimately, these changes resulted in increased neuronal excitability and neurotransmitter release to functionally enhance dynamic food intake during energy state transitions. Collectively, MFF-dependent mitochondrial fission links cell-type-specific neuronal mitochondrial dynamics via mitochondrial Ca2+ handling to control systemic metabolism.
    Keywords:  AgRP; MFF; calcium; metabolism; mitochondria; neuronal activity
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.038
  50. Neurol Sci. 2026 May 07. pii: 475. [Epub ahead of print]47(6):
    Mitochondrial complex III deficiency nuclear type 2: a case report and analysis of clinical onset age-related phenotypic features.
    Shih-Chun Lan, Yung-Yee Chang, Shu-Fang Chen, Ying-Fa Chen, Min-Yu Lan.
       CASE PRESENTATION: Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is a rare inherited neurometabolic disease. A 34-year-old male had neuropsychiatric episodes, progressive cerebellar degeneration, myopathy, polyneuropathy, and brain stem and basal ganglion lesions since childhood. Muscle biopsy revealed mitochondrial abnormalities. Two novel TTC19 pathogenic variants were detected.
    LITERATURE REVIEW: To analyze phenotypic characteristics of MC3DN2 related to clinical onset age, neurological presentation and brain MRI regarding infantile and childhood-onset (ICO) and adolescent and adult-onset (AAO) disease in a cohort composed of our patient and the cases reported in the literature were compared. It revealed that, clinically, cerebellar ataxia was common in both groups, nystagmus was more frequently noted in AAO patients, and psychiatric disturbances were more common in ICO patients. Regarding MRI findings, basal ganglion lesions were more prevalent in ICO patients, and inferior olive lesions were more frequent in AAO patients.
    DISCUSSION: These conspicuous phenotypic features of MC3DN2 may suggest diagnosis of this distinctive disease. The differences in clinical features and brain lesions associated with clinical onset age could provide crucial insights into the phenotypic landscape of MC3DN2.
    Keywords:   TTC19 ; Cerebellar ataxia; Leigh syndrome; Mitochondrial complex III deficiency nuclear type 2; Mitochondrial disease
    DOI:  https://doi.org/10.1007/s10072-026-09073-6
  51. J Am Chem Soc. 2026 May 08.
    Molecular Principles of Gating Proton Transport in the Antiporter Modules of Respiratory Complex I.
    Sofia Badolato, Sarah C Rossmann, Joana Pereira, Hyunho Kim, Ville R I Kaila.
      The respiratory Complex I is a highly intricate redox-driven proton pump that powers oxidative phosphorylation across all domains of life. Yet, despite major efforts, its long-range energy transduction principles remain much debated. Here, we study the molecular principles of proton transport by engineering the antiporter modules of Complex I. By combining directed mutagenesis with time-resolved spectroscopy and molecular dynamics (MD) simulations, we identify conserved residues along the proton channels that control the rate of proton transfer across proteoliposome membranes. The antiporter modules catalyze this tightly regulated proton transport by transient water wires that follow intrinsic electric fields along the proton channels. Based on MD simulations, we identify conserved gating sites, established by nonpolar residues, which modulate the hydration and electric field effects underlying the proton transport upon mutation. On a general level, our findings highlight how the modular energy-transduction machinery of Complex I employs a combination of electrostatic and conformational coupling principles to catalyze long-range proton transport, with distinct similarities to other enzymes.
    DOI:  https://doi.org/10.1021/jacs.6c05956
  52. Nat Commun. 2026 May 07. pii: 4196. [Epub ahead of print]17(1):
    Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.
    Gisele A Andree, Luca J Stier, Kerstin Schmiederer, Alina S Thielen, Luis Schmid, Samuel A Maiwald, Karthik V Gottemukkala, Jiale Du, Susanne von Gronau, Claudia Strasser, Judith Müller, Lukas T Henneberg, Camille Guyot, Gary Kleiger, Matthias Mann, Peter J Murray, Brenda A Schulman.
      Cellular responses to amino acid fluctuations often hinge on ubiquitin-mediated control of metabolic enzymes, yet the underlying E3 ligase pathways remain poorly defined. Using quantitative proteomics and active cullin-RING ligase (CRL) profiling, we identify LRRC58 as a cysteine-responsive substrate receptor whose stability increases sharply under cysteine starvation. Proteomics reveals an inverse relationship between LRRC58 and the metabolic enzyme cysteine dioxygenase 1 (CDO1), suggesting a cysteine-linked regulatory axis. Biochemical reconstitution and cryo-EM structures show that LRRC58 forms an active CUL2- or CUL5-based CRL that selectively positions CDO1 for ubiquitylation at Lys8. Disease mutant versions of CDO1 mapping to the LRRC58 interface and impaired for the endogenous ubiquitylation pathway were degraded through orthogonal targeting by a VHL-based degrader. Together, our proteomics-guided discovery pipeline, cellular stability studies, and structural analyses uncover a metabolically-tuned LRRC58-CDO1 pathway that links cysteine availability to selective proteasomal turnover, reveals principles of metabolite-regulated CRL activity, and showcases mechanisms distinguishing endogenous and targeted protein degradation.
    DOI:  https://doi.org/10.1038/s41467-026-72524-3
  53. Nat Commun. 2026 May 07.
    Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
    Xiao-Wen Zhang, Xiao-Ming Ye, Ran Wang, Yong-Dong Guo, Ling Li, Yang Chen, Ting-Ting Liu, Xiao-Qing Zhou, Yu-Qi Wang, Zhong-Yao Li, Zhi-Yuan Lu, Zhi-Yong Du, Wei Zhou, Bo Han, Peng-Fei Tu, Qi-Xin Chen, Chun-Hong Zheng, Ke-Wu Zeng.
      Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.
    DOI:  https://doi.org/10.1038/s41467-026-72779-w
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