bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2025–10–05
forty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Interconnectivity of mitochondrial protein biogenesis and quality control.
  2. Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
  3. A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.
  4. Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.
  5. Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
  6. DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.
  7. The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
  8. The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.
  9. Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.
  10. Case Report: Biallelic variants in MRPS36, encoding a component of the 2-oxoglutarate dehydrogenase complex, cause leigh syndrome.
  11. Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.
  12. Predizione del tipo di mutazione nelle malattie mitocondriali primarie tramite modelli di machine learning applicati a dati clinici non genetici né istologici.
  13. Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.
  14. Health-related quality of life in patients with mitochondrial disease and their carers.
  15. Association between mitochondrial DNA copy number and the risk of Parkinson's disease: a meta-analysis and Mendelian randomization study.
  16. A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
  17. Mitochondrial dynamics and pore formation in regulated cell death pathways.
  18. A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
  19. Successful treatment of congenital sideroblastic anemia with low-dose decitabine in a patient with NDUFB11 gene mutation (c.276_278del): A case report.
  20. A zebrafish model of nicotinamide adenine dinucleotide (NAD+) deficiency-derived congenital disorders.
  21. Carabrone inhibits Gaeumannomyces tritici growth by targeting mitochondrial complex I and destabilizing NAD⁺/NADH homeostasis.
  22. MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
  23. Absolute quantification of TCA cycle intermediates in mouse ocular tissues reveals distinct tissue- and sex-specific mitochondrial metabolism.
  24. Mitochondria as a Therapeutic Target in Metabolic Disorders.
  25. Integrating Long-Read Nanopore Sequencing for Precision Resolution of Genomic Variants in Dystonia.
  26. Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
  27. Ophthalmological signs and sensorimotor evaluation in mitochondrial chronic progressive external ophthalmoplegia: a multidisciplinary prospective study.
  28. Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations.
  29. A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy.
  30. Engineering Artificial Mitochondria with Self-Amplifying Proton Generation for Autonomous Energy Supply and Metabolic Coupling in Artificial Cells.
  31. Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
  32. Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models.
  33. A needed nomenclature for nucleosomes.
  34. Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
  35. Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM, ACADVL and SLC22A5 Genes.
  36. Geometrically-engineered human motor assembloids-on-a-chip for neuromuscular interaction readout and hypoxia-driven disease modeling.
  37. Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders.
  38. Spatially resolved in situ profiling of mRNA life cycle at transcriptome scale in intact cells and tissues using STARmap PLUS, RIBOmap and TEMPOmap.
  39. Somewhere to go: a position paper on addressing gaps in transition care for adults with childhood-onset rare diseases.
  40. Teaching NeuroImage: Multiple Symmetric Lipomatosis as a Manifestation of Mitochondrial Cytopathy.
  41. DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.
  1. Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]
    Interconnectivity of mitochondrial protein biogenesis and quality control.
    Abi S Ghifari, Carmela Vazquez-Calvo, Andreas Carlström, Martin Ott.
      Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.
    Keywords:  mitochondria; proteases; protein import; proteolysis; proteostasis; translation
    DOI:  https://doi.org/10.1016/j.tibs.2025.09.004
  2. Nat Commun. 2025 Sep 30. 16(1): 8685
    Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
    Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-63813-4
  3. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2506761122
    A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.
    Deborah G Murdock, Kevin A Janssen, Kierstin Keller, Katherine L Mitchell, Maina Beauplan, William T O'Brien, Lia D'Alessandro, Jeffrey A Haltom, Douglas C Wallace.
      MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron-sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.
    Keywords:  genetics; iron; mitochondrial disease; mitochondrial fatty acid synthesis; mouse model
    DOI:  https://doi.org/10.1073/pnas.2506761122
  4. Neural Regen Res. 2025 Sep 29.
    Mitochondrial DNA homeostasis: A novel therapeutic target for neurodegenerative diseases.
    Tingting Fu, Xinyi Chen, Shuting Zhang, Ying Fu, Lin Huang, Wandi Xiong.
       ABSTRACT: The mitochondrial genomic homeostasis is essential for the function of the oxidative phosphorylation system and cellular homeostasis. Mitochondrial DNA is particularly susceptible to aging-related oxidative stress due to the lack of a histone coat. Disturbances in mitochondrial DNA may contribute to functional decline during the aging process and in neurodegenerative diseases, leading to further impairment of mitochondrial DNA and initiating a vicious cycle. To date, it remains unclear how disturbed mitochondrial DNA is involved in the etiology of pathological aging and neurodegenerative diseases. The purpose of this review is to clarify the crucial roles of mitochondrial DNA homeostasis in the pathogenesis of neurodegenerative diseases. Mitochondrial DNA is distributed within nucleoids and is then transcribed into polycistronic mitochondrial DNA molecules within the mitochondrial granule region. Within the ultrastructure of the mitochondrial nucleoid and granule, a group of essential mitochondrial proteins involved in DNA replication, DNA transcription, RNA translation, RNA surveillance, and RNA degradation plays a crucial role in maintaining mitochondrial structure, genome integrity, and mitochondrial DNA processing. The uniparentally inherited mitochondrial DNA undergoes heritable polyploid variations, which include homoplasmy and heteroplasmy. Accumulating mitochondrial DNA alterations, such as deletions, point mutations, and methylations, occur during the pathogenic processes of neurodegenerative diseases. The increased mitochondrial DNA alterations can be propagated by the rise of deleterious heteroplasmy in neurodegenerative diseases, ultimately resulting in impairment to the oxidative phosphorylation system, biogenesis defects, and cellular metabolic dysfunction. Therefore, developing appropriate gene editing tools to rectify aberrant alterations in mitochondrial DNA and targeting the key proteins involved in maintaining mitochondrial DNA homeostasis can be considered promising therapeutic strategies for neurodegenerative diseases. Although therapeutic strategies targeting mitochondrial DNA in diseases show great potential, challenges related to efficacy and safety require a better understanding of the mechanisms underlying mitochondrial DNA alterations in aging and neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; heteroplamy; mitochondrial DNA; mitochondrial DNA mutation; mitochondrial genome; mitochondrial haplogroup; mitochondrial homeostasis; neurodegenerative diseases
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00495
  5. Front Cell Neurosci. 2025 ;19 1635775
    Establishment of human Leber's hereditary optic neuropathy model using iPSC-derived retinal organoids.
    Kota Aoshima, Yuya Takagi, Michinori Funato, Yoshiki Kuse, Shinsuke Nakamura, Masamitsu Shimazawa.
      Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease caused by mitochondrial DNA mutations, leading to central vision loss and retinal ganglion cell (RGC) degeneration. Progress in understanding LHON and developing treatments has been limited by the lack of human-like models. In this study, we aimed to establish a human retinal model of LHON using retinal organoids (ROs) from LHON patient-derived induced pluripotent stem cells (LHON-iPSCs). We first confirmed LHON-iPSCs were successfully differentiated into ROs (LHON-ROs). LHON-RO showed a reduction in RGC numbers and the density of neural axons. Additionally, both mitochondrial membrane potential and ATP production were decreased in LHON-RO. Finally, treatment with idebenone, the only approved therapeutic agent for LHON, improved RGC numbers in LHON-RO. This model replicates key clinical features of LHON, including RGC and axonal loss, and demonstrates idebenone's therapeutic potential. Furthermore, a comprehensive analysis of the LHON-RO model revealed impaired mitophagy, suggesting novel therapeutic targets for LHON. Thus, the LHON-RO model offers a valuable platform for studying LHON pathogenesis and evaluating treatments.
    Keywords:  Leber’s hereditary optic neuropathy; in vitro disease modeling; mitochondrial disease; mitophagy; retinal organoid
    DOI:  https://doi.org/10.3389/fncel.2025.1635775
  6. Nat Metab. 2025 Sep 30.
    DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.
    Saber H Saber, Nyakuoy Yak, Xuan Ling Hilary Yong, Yih Tyng Bong, Hannah Leeson, Chuan-Yang Dai, Tobias Binder, Siyuan Lu, Reshinthine Purushothaman, An-Sofie Lenaerts, Leonardo Almeida-Souza, Lidiia Koludarova, Safak Er, Irena Hlushchuk, Arnaud Gaudin, Sachin Singh, Tuula A Nyman, Jeffrey R Harmer, Steven Zuryn, Ernst Wolvetang, Gert Hoy Talbo, Mikko Airavaara, Brendan J Battersby, Ashley J van Waardenberg, Victor Anggono, Giuseppe Balistreri, Merja Joensuu.
      Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.
    DOI:  https://doi.org/10.1038/s42255-025-01367-x
  7. Sci Adv. 2025 Oct 03. 11(40): eadw7376
    The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
    Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.
      Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
    DOI:  https://doi.org/10.1126/sciadv.adw7376
  8. Neurochem Res. 2025 Oct 04. 50(5): 317
    The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson's Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress.
    Vaishali Walecha, Pratibha M Luthra.
      The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the "triad hypothesis," offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte-neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.
    Keywords:  Astrocytic mitochondria; Calcium signalling; Ferroptosis; Mitochondrial dysfunction; Mitochondrial transfer; Neurodegeneration; Neuroinflammation; Neuron-astrocyte interaction; Oxidative stress; Parkinson’s disease (PD); α-Synuclein aggregation
    DOI:  https://doi.org/10.1007/s11064-025-04559-9
  9. Pediatr Res. 2025 Oct 02.
    Identification of novel NDUFA3 variants in a patient with mitochondrial disorders.
    Yu Sun, Xiujuan Wei, Bing Xiao, Yongfeng Luo, Ya Wang, Ripeng Liu, Yongkun Zhan, Xiantao Ye, Xudong Cai, Shiyi Xu, Jianxin Lyu, Hezhi Fang, Yongguo Yu.
       BACKGROUND: Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism.
    METHODS: We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient's cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption.
    RESULTS: The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient's cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development.
    CONCLUSIONS: Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum.
    IMPACT: NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder. A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects. NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation. Zebrafish with ndufa3 knock down manifests delayed locomotor development. With this reported patient, the relationship between the gene and disease can be upgraded from "limited" to "moderate".
    DOI:  https://doi.org/10.1038/s41390-025-04403-4
  10. Front Pediatr. 2025 ;13 1608840
    Case Report: Biallelic variants in MRPS36, encoding a component of the 2-oxoglutarate dehydrogenase complex, cause leigh syndrome.
    Huafang Jiang, Chaolong Xu, Zhimei Liu, Ruoyu Duan, Xingfeng Yao, Xiaona Fu, Jiatong Xu, Xuejing Kang, Tenghui Yu, Yuanyuan Wang, Fang Fang.
       Background: The MRPS36 gene encodes the E4 subunit of the 2-oxoglutarate dehydrogenase complex (OGDHC), a critical enzyme in the tricarboxylic acid cycle. OGDHC deficiency can lead to metabolic disorders with a clinical spectrum ranging from fatal neonatal lactic acidosis to variable degrees of global developmental delay and movement disorders. To date, a homozygous MRPS36 variant has been reported as a novel cause of Leigh syndrome in only two siblings, who presented with developmental delay, movement disorders, bilateral striatal necrosis, and reduced OGDHC activity.
    Case presentation: We report a third case of Leigh syndrome associated with MRPS36 variants in a 2-year-old boy. The patient exhibited with global developmental delay, dystonia, early-onset chorea, and elevated serum lactate levels. Follow-up brain magnetic resonance imaging at 2 years revealed progressive degenerative lesions in the bilateral basal ganglia. Muscle biopsy showed abnormal mitochondrial accumulation beneath the sarcolemma, and the oxygen consumption rate was reduced in skin fibroblasts. Whole-exome sequencing identified two novel compound heterozygous MRPS36 variants: c.42+1G>A (p.?) and c.296G>C (p.Arg99Pro).
    Conclusion: This case supports MRPS36 as a novel pathogenic cause of Leigh syndrome, further expanding the genetic spectrum of the disorder. Key clinical features include developmental delay, involuntary movement disorders, progressive basal ganglia atrophy, and a slowly progressive disease course.
    Keywords:  2-oxoglutarate dehydrogenase complex; Leigh syndrome; MRPS36 gene; OGDHC; case report; choreic movement; movement disorder
    DOI:  https://doi.org/10.3389/fped.2025.1608840
  11. Pharmacol Res. 2025 Sep 25. pii: S1043-6618(25)00398-6. [Epub ahead of print]221 107973
    Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.
    Bernard Ribalet, Scott John, Madeleine G Milner, Leia Salongo, Ambre M Bertholet.
      In mitochondria, the energy derived from the proton gradient across the mitochondrial inner membrane (IMM) is converted into ATP and heat. For these conversions to occur, H+ is pumped out of the matrix via the electron transport chain (ETC) and then re-enters either via the ATP synthase to produce ATP or via the ADP/ATP carrier (AAC) to release heat. Due to its dual functions of ADP/ATP exchange and H+ transport, AAC may be considered a major regulator of the energy distribution of mitochondria between ATP synthesis and thermogenesis. Using real-time imaging of pH with a fluorescent pH probe targeted to the mitochondrial matrix, we investigated in a myoblast cell model how H+ fluxes across the IMM are regulated by AAC and the ATP synthase. Our data show that activation of AAC-dependent H+ transport by the mitochondrial uncoupler BAM15 causes an acidification of the matrix followed by a re-alkalization phase due to the reversed activity of the ATP synthase. Similar re-alkalization and reversal of ATP synthase activity were observed after acidification caused by inhibition of the electron transport chain. Lastly, the discovery that strong protonophoric activity independent of AAC suppresses the re-alkalization phase and consequently the reverse action of the ATP synthase, suggests the need for strict control of the H+ flux through the IMM by AAC. Thus, real-time imaging of matrix pH reveals a functional interaction between AAC and the ATP synthase for the control of H+ fluxes across the IMM.
    Keywords:  ADP/ATP carrier; ATP synthase; BAM15; Electron transport chain; FCCP; Mitochondria; PH sensor; Proton transport; Uncoupling protein
    DOI:  https://doi.org/10.1016/j.phrs.2025.107973
  12. Recenti Prog Med. 2025 Oct;116(10): 613-614
    Predizione del tipo di mutazione nelle malattie mitocondriali primarie tramite modelli di machine learning applicati a dati clinici non genetici né istologici.
    Sara Mazzucato, Piervito Lopriore, Francesco Daddoveri, Costanza Lamperti, Valerio Carelli, Olimpia Musumeci, Serenella Servidei, Silvestro Micera, Michelangelo Mancuso, Andrea Bandini.
      This study shows that machine learning can accurately distinguish between mitochondrial and nuclear DNA mutations in primary mitochondrial diseases using only non-genetic and non-histological clinical data. While language models underperform in comparison, they show potential as complementary diagnostic tools.
    DOI:  https://doi.org/10.1701/4573.45801
  13. HGG Adv. 2025 Sep 29. pii: S2666-2477(25)00128-9. [Epub ahead of print] 100525
    Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.
    Brianna L DiSanza, Giulia S Porcari, Livia Sertori Finoti, Leonardo Ramos-Rodriguez, Devin M Burris, Justin A McDonough, Gang Ning, Grace Fagan, Guy T Helman, Erin Weiss, Ryan J Taft, Amy Pizzino, Matthew T Whitehead, Amy Waldman, Cas Simons, Xilma Ortiz-Gonzalez, William C Skarnes, Adeline Vanderver, Elizabeth J Bhoj, Rebecca C Ahrens-Nicklas.
      Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAA), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.(Phe264Leu); c.1042G>A p.(Glu348Lys)) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1-disease neurons, suggesting a downstream impact on electron-transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.
    DOI:  https://doi.org/10.1016/j.xhgg.2025.100525
  14. J Med Genet. 2025 Sep 27. pii: jmg-2025-110896. [Epub ahead of print]
    Health-related quality of life in patients with mitochondrial disease and their carers.
    Deborah Schofield, Joshua Kraindler, Katherine Lim, Owen Tan, Sameen Haque, Karen Crawley, Sarah West, Adam Percival, Jayamala Parmar, Rupendra Shrestha, Carolyn Sue.
       BACKGROUND: Mitochondrial diseases are a group of rare, chronic disorders with a significant disease burden; however, there is limited knowledge about their effects on the health-related quality of life (HRQoL) of patients and their carers. This study estimates HRQoL among adult patients with mitochondrial diseases and their carers, using the Assessment of Quality-of-Life 8D (AQoL-8D), a validated instrument for measuring health utilities.
    METHODS: Ninety-nine adult patients and 24 carers were recruited to the Economic and Psychosocial Impacts of Caring for Families Affected by Mitochondrial Disease (EPIC-MITO) Study, based in New South Wales, Australia.
    RESULTS: Adult patients exhibited significantly lower utility values (0.52) compared with age-adjusted and gender-adjusted population norms (0.80; p<0.001). Regression analysis shows that mental health disorders, sleep disorders, financial stress and female gender were associated with reduced HRQoL. Carers also demonstrated AQoL-8D utility values (0.70) significantly below age-adjusted and gender-adjusted population norms (0.81; p=0.01) reflecting the broader burden of mitochondrial diseases on families.
    CONCLUSION: With increasing use of genetic testing and genomic sequencing, as well as hope for gene therapies, health utility values will be necessary for economic evaluations of new interventions for mitochondrial disease. This paper shows the substantial impact on HRQoL of mitochondrial disease measured through utilities. The utility values from this paper can inform future economic evaluations for interventions for patients with mitochondrial disease. Further, the paper demonstrated that mitochondrial disease not only reduces the HRQoL of patients but also impacts the HRQoL of carers.
    Keywords:  Economics; Neuromuscular Diseases
    DOI:  https://doi.org/10.1136/jmg-2025-110896
  15. BMC Neurol. 2025 Sep 29. 25(1): 390
    Association between mitochondrial DNA copy number and the risk of Parkinson's disease: a meta-analysis and Mendelian randomization study.
    Haoyang Zheng, Duo Zhang, Yong Gan, Yuyi Wu, Wei Xiang.
      
    Keywords:  Copy number; Mendelian randomization; Meta-analysis; Mitochondrial DNA; Parkinson's disease
    DOI:  https://doi.org/10.1186/s12883-025-04400-4
  16. J Hum Genet. 2025 Oct 03.
    A novel homozygous COX6A1 variant causes axonal charcot-marie-tooth disease, developmental delays and mitochondrial dysfunction.
    Qianyun Cai, Haijiao Wang, Rong Luo, Xiao Qian, Zhongjie Zhou.
      Mitochondrial complex IV (cytochrome c oxidase, COX) is essential for oxidative phosphorylation, and pathogenic variants of COX-related genes, such as COX6A1, are associated with neuromuscular disorders. While recessive COX6A1 variants are linked to Charcot-Marie-Tooth disease (CMT), the phenotypic spectrum and molecular mechanism remain incompletely understood. Here we report a 2-year-4-month-old girl who presented with global developmental delay, axonal CMT disease, and elevated lactate levels. WES revealed a rare homozygous COX6A1 variant (NM_004373.4: c.329 A > T, p.110Leuext41) that is absent in population databases. This variant is 41 amino acids longer than the wild-type protein. Functional assays demonstrated significantly reduced mutant protein levels (p < 0.01), supporting the pathogenicity of this mutation. The patient experienced rapid decompensation and died following febrile illness at the age of 3.5 years. This study revealed a novel pathogenic COX6A1 variant that causes developmental delay and mitochondrial dysfunction, highlighting stop-loss mutations as a mechanism of disease. We report the first COX6A1 stop-loss variant, and our findings expand the phenotypic and genetic spectrum of COX6A1-related disorders.
    DOI:  https://doi.org/10.1038/s10038-025-01411-4
  17. Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00219-1. [Epub ahead of print]
    Mitochondrial dynamics and pore formation in regulated cell death pathways.
    Lisa Hohorst, Uris Ros, Ana J Garcia-Saez.
      Mitochondria act as central hubs for cell death signaling. During apoptosis and regulated necrosis (pyroptosis, necroptosis, and ferroptosis), mitochondria undergo drastic changes including membrane permeabilization, fragmentation, and loss of membrane potential. However, dissection of the mechanisms underlying these processes is challenging because they involve remodeling of mitochondrial membranes coupled to the assembly of protein complexes whose dynamics are difficult to capture. We discuss progress in our understanding of mitochondrial alterations in cell death and highlight state-of-the-art experimental approaches to study them. We focus on advanced single-molecule and correlative microscopy methods which have recently provided unprecedented details about the dynamics and structure of protein complexes in mitochondria and their impact on membrane organization.
    Keywords:  apoptosis; correlative microscopy; mitochondria dynamics; mitochondrial outer membrane permeabilization (MOMP); pore formation; single-molecule microscopy
    DOI:  https://doi.org/10.1016/j.tibs.2025.09.001
  18. Cell Biochem Funct. 2025 Oct;43(10): e70125
    A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.
    Hailun He, Xin Zhang, Lidan Xiong, Xiao Qin.
      FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS-STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.
    Keywords:  FUNDC1; MAMs; metabolic diseases; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1002/cbf.70125
  19. Curr Res Transl Med. 2025 Sep 09. pii: S2452-3186(25)00051-0. [Epub ahead of print]73(4): 103542
    Successful treatment of congenital sideroblastic anemia with low-dose decitabine in a patient with NDUFB11 gene mutation (c.276_278del): A case report.
    Juan Wang, Heng Li, Nan Lv, Min Wang, Hongyu Zhao.
       BACKGROUND: Congenital sideroblastic anemias (CSAs) are an inherited group of blood disorders due to defects of mitochondrial proteins. The NDUFB11 gene is essential for the assembly of mitochondrial complex Ⅰ protein. Mutations in the NDUFB11 gene can cause sideroblastic anemia with hyperlacticemia, microphthalmia, cardiomyopathy and encephalomyopathy with limited therapeutic options.
    CASE PRESENTATION: We reported a 35-year-old man with congenital sideroblastic anemia, skeletal dysplasias and hyperlacticemia. The skeletal muscle stains indicated probability of mitochondrial disorders. By whole-exome sequencing, we identified a mutation (c.276_278delCTT) in NDUFB11 gene in this patient which was inherited from his mother. He was unresponsive to the treatment of vitamin B2, vitamin B6, Coenzyme Q10, idebenone, or EPO but achieved hemoglobin concentration rise, transfusion independence and improvement of quality life after treated with low dose decitabine.
    CONCLUSIONS: We proposed that epigenetic factors might play a role in pathogenesis in patients with c.276_278del (p.F93del) mutation in NDUFB11 gene and low dose decitabine may be a novel treatment in CSA patients with c.276_278del (p.F93del) mutation in NDUFB11 gene.
    Keywords:  Congenital sideroblastic anemias; Low dose decitabine; Mitochondrial disorder; NDUFB11; Whole-exome sequencing
    DOI:  https://doi.org/10.1016/j.retram.2025.103542
  20. Dev Biol. 2025 Sep 30. pii: S0012-1606(25)00280-5. [Epub ahead of print]
    A zebrafish model of nicotinamide adenine dinucleotide (NAD+) deficiency-derived congenital disorders.
    Visakuo Tsurho, Carla Gilliland, Jessica Ensing, Elizabeth A VanSickle, Nathan J Lanning, Paul R Mark, Stephanie Grainger.
      Developmental NAD+ deficiency is associated with diverse congenital malformations. Congenital NAD deficiency disorder (CNDD) is a multisystem developmental condition characterized by cardiac, renal, vertebral, and limb anomalies, among others. It is caused by biallelic pathogenic variants in genes involved in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway. CNDD anomalies overlap with clinical features described in vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association, suggesting a possible shared etiological link through NAD+ deficiency. However, the aberrant developmental mechanisms of NAD+-deficient congenital anomalies remain poorly understood. To dynamically explore NAD+-deficiency-induced congenital malformations, we developed a zebrafish model of NAD+ disruption. Zebrafish embryos treated with 2-amino-1,3,4-thiadiazole (ATDA), a known NAD+ metabolism disruptor, exhibited cardiac, tail, spinal cord, and craniofacial defects, which were partially rescued by nicotinamide (NAM) in a dose-dependent manner. Our work establishes zebrafish as a useful model for investigating how NAD+ deficiency contributes to multisystem congenital anomalies.
    Keywords:  2-Amino-1,3,4-thiadiazole (ATDA); birth defects; congenital NAD deficiency disorder (CNDD); nicotinamide (NAM); nicotinamide adenine dinucleotide (NAD(+)); vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association; zebrafish
    DOI:  https://doi.org/10.1016/j.ydbio.2025.09.022
  21. PLoS Pathog. 2025 Oct 03. 21(10): e1013567
    Carabrone inhibits Gaeumannomyces tritici growth by targeting mitochondrial complex I and destabilizing NAD⁺/NADH homeostasis.
    Xingyu Ren, Jing Bai, Yingying Han, Jiaying Xu, Yingchen Liu, Zhiqing Ma, Yong Wang, Juntao Feng.
      The excessive and irrational use of commercial fungicides has led to escalating drug resistance in phytopathogens, necessitating the discovery of novel antifungal targets and strategies. Plant secondary metabolites, serving as natural chemical defenses against pathogen invasion, offer promising scaffolds and potential targets for developing innovative crop protection approaches. This study elucidates the antifungal mechanism of the natural sesquiterpene lactone carabrone against Gaeumannomyces tritici through integrated multi-omics analyses. Time-series transcriptomic profiling revealed that carabrone significantly suppresses the oxidative phosphorylation (OXPHOS) pathway and disrupts nicotinate/nicotinamide metabolism, resulting in a reduced NAD⁺/NADH (NAD+, Oxidized nicotinamide adenine dinucleotide; NADH, Reduced nicotinamide adenine dinucleotide) ratio. Orthogonal elevation of NAD⁺ levels through exogenous supplementation diminished fungal susceptibility to carabrone, establishing a direct link between NAD⁺/NADH homeostasis and its antifungal activity. Activity-based protein profiling (ABPP), gene silencing screens, and physiological-biochemical validations collectively demonstrated that carabrone specifically inhibits the electron transport chain (ETC) rather than ATP synthase to regulate NAD⁺/NADH balance. Further evidence from pyruvate supplementation, expression of the yeast non-proton-pumping NADH dehydrogenase ScNDI1, and enzymatic assays confirmed that carabrone directly targets mitochondrial respiratory chain complex I, thereby destabilizing NAD⁺/NADH homeostasis and suppressing G. tritici growth. This work first establishes complex I as the direct antifungal target of carabrone, revealing its lethal mechanism involving complex I inhibition-mediated blockade of NADH oxidation, followed by oxidative stress induction and energy metabolism collapse. Additionally, we demonstrate that ScNDI1 serves as a critical tool for screening and validating complex I-targeted fungicides. These findings provide both a lead scaffold for developing novel complex I inhibitors and a systematic framework for antifungal agent validation, offering theoretical support to combat emerging fungal resistance challenges.
    DOI:  https://doi.org/10.1371/journal.ppat.1013567
  22. Nat Commun. 2025 Oct 03. 16(1): 8831
    MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
    Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer, Christian Wolfrum.
      Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-63880-7
  23. bioRxiv. 2025 Sep 27. pii: 2025.09.25.678562. [Epub ahead of print]
    Absolute quantification of TCA cycle intermediates in mouse ocular tissues reveals distinct tissue- and sex-specific mitochondrial metabolism.
    Cloe Ratliff, David Hansman, Tuan Ngo, Yinxiao Xiang, Artjola Puja, Mark Eminhizer, Jinyu Lu, Isabella Mascari, Diana Alabdallat, Jianhai Du.
       Objective: Mitochondrial tricarboxylic acid (TCA) cycle is central to energy production and redox balance in the eye, which must sustain high metabolic activity to support vision. Retinal neurons, the retinal pigment epithelium (RPE), cornea, and lens each have distinct physiological roles and metabolic demands, yet the absolute concentrations of key TCA intermediates and their variation by tissue, sex, and time of day are not well-defined.
    Methods: Targeted gas chromatography-mass spectrometry was employed to quantify the absolute concentrations of TCA cycle metabolites in mouse ocular tissues collected at 10 AM and 2 PM to capture diurnal variations. Key metabolite ratios were subsequently calculated to provide insight into TCA cycle dynamics across eye tissues.
    Results: The retina showed the highest concentrations of TCA metabolites among all ocular tissues, particularly succinate, citrate, and malate, consistent with its high energy demands. The RPE/choroid demonstrated well-balanced intermediates with the highest α-ketoglutarate (α-KG)/Isocitrate ratio, reflecting its efficient mitochondrial oxidation and reductive carboxylation. Corneal metabolism was featured by dominant malate, especially in females, suggesting a metabolic adaptation for redox regulation and oxidative stress defense. The lens had uniformly low metabolite levels except for succinate, indicating minimal mitochondrial activity under physiologically low oxygen conditions. Notably, both the cornea and lens showed significant sex-dependent and diurnal variations in TCA cycle intermediates.
    Conclusion: This study demonstrates distinct tissue-specific mitochondrial metabolism in the eye, reflecting the unique functional and biochemical demands of each tissue. These metabolic signatures may underlie their susceptibility to mitochondrial dysfunction in various ocular diseases.
    DOI:  https://doi.org/10.1101/2025.09.25.678562
  24. Mini Rev Med Chem. 2025 Sep 29.
    Mitochondria as a Therapeutic Target in Metabolic Disorders.
    Youde Cai, Fang Gan, Yunzhi Chen, Qiansong He, Wei Chen, Zhongyong Peng, Ling Gong.
      Mitochondria, commonly termed the 'cellular powerhouse', produce the majority of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In addition to their role in energy synthesis, mitochondria are crucial for maintaining calcium homeostasis, mediating cellular signaling, regulating cell proliferation and apoptosis, and supporting various other physiological processes. In recent years, mitochondria have gained prominence as a critical target for the treatment of metabolic disorders. Research has demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of metabolic diseases, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular diseases, and endocrine tumors. Consequently, understanding the mechanisms of mitochondrial homeostatic imbalance and developing mitochondria-targeted therapeutics hold promise for innovative treatments of metabolic disorder-related diseases. This article seeks to elucidate recent advancements in the understanding of mitochondrial dysfunction's role in metabolic diseases and offers a comprehensive overview of current therapeutic strategies and approaches for addressing this dysfunction.
    Keywords:  Mitochondria; bioenergetics; cellular signaling; metabolism; redox biology; therapeutic target.
    DOI:  https://doi.org/10.2174/0113895575403490250917111723
  25. Mov Disord. 2025 Sep 30.
    Integrating Long-Read Nanopore Sequencing for Precision Resolution of Genomic Variants in Dystonia.
    Ugo Sorrentino, Martin Pavlov, Nazanin Mirza-Schreiber, Melanie Brugger, Theresa Brunet, Eugenia Tsoma, Alice Saparov, Ivana Dzinovic, Philip Harrer, Antonia M Stehr, Matias Wagner, Erik Tilch, Barbara Wallacher, Shiraz Alhasan, Anne Koy, Alessio Di Fonzo, Miriam Kolnikova, Katarina Kusikova, Petra Havrankova, Raushana Tautanova, Sandy Lösecke, Sebastian Eck, Sylvia Boesch, Jan Necpal, Matej Skorvanek, Robert Jech, Holger Prokisch, Juliane Winkelmann, Konrad Oexle, Elisabeth Graf, Michael Zech.
       BACKGROUND: Although many individuals with dystonia present with features indicative of single-gene etiologies, obtaining definitive genetic diagnoses can be challenging.
    OBJECTIVE: We assessed the value of nanopore-based long-read sequencing (LRS) in achieving molecular clarification of dystonic syndromes.
    METHODS: From a large dystonia cohort with short-read sequencing (SRS) data, 14 cases with unclear, difficult-to-evaluate, or missing causative variants were recruited. Long-read whole-genome sequencing was performed according to Oxford Nanopore Technologies (ONT) protocols.
    RESULTS: ONT sequencing produced long-range haplotypes, variant calls inaccessible to short-read technology, as well as methylation data. Phase inference allowed for changes in variant classification, establishing compound heterozygosity of causative variants in four cases. We illustrate an important advantage of LRS compared with SRS in (re)defining the identity of dystonia-causing structural variants and repeat expansions for seven individuals. One patient was found to harbor a novel exonic LINE-1 insertion in SGCE, expanding the genetic mechanism in myoclonus-dystonia. ONT data also provided unexpected insights into apparent mosaic expanded repeats in FMR1 in a subject with isolated focal dystonia. We further showed that LRS outperformed SRS in avoiding erroneous calls resulting from confounding pseudogene sequences and in discovering pathogenic alterations missed by conventional pipeline utilization (three cases). Moreover, simultaneous methylome analysis aided in directing the interpretation of three variants, including a KMT2B variant of uncertain significance that was reclassified as causal by LRS-based episignature profiling.
    CONCLUSIONS: ONT-based LRS uniquely improves analysis of dystonia-associated variations that had not previously been resolved by SRS, implying broad utility for future exploration of the molecular origins of the condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  complex structural variants; dystonia; long‐range phasing; long‐read sequencing; nanopore technology; repeat expansions
    DOI:  https://doi.org/10.1002/mds.70072
  26. EMBO Mol Med. 2025 Sep 29.
    Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s44321-025-00306-3
  27. BMC Ophthalmol. 2025 Sep 30. 25(1): 520
    Ophthalmological signs and sensorimotor evaluation in mitochondrial chronic progressive external ophthalmoplegia: a multidisciplinary prospective study.
    Gustavo Savino, Federico Giannuzzi, Valentina Cima, Davide Brando, Claudia Fossataro, Serenella Servidei, Maria Cristina Savastano, Guido Primiano.
       BACKGROUND: Primary mitochondrial myopathies (PMM) are disorders that involve defects in oxidative phosphorylation (OXPHOS) and impair mainly, but not exclusively, skeletal muscles. Progressive external ophthalmoplegia (PEO), eyelid ptosis, exercise intolerance and skeletal muscle weakness are the most common symptoms of myopathy in mitochondrial diseases, impairing ocular motility and visual abilities.
    METHODS: Twenty-five patients underwent complete ophthalmological examination, including best corrected visual acuity (BCVA), ptosis evaluation, dilated fundus examination, and orthoptic examinations, including cover and cover-uncover test, ocular motility analysis, fusional amplitude (FA) vergence for near and for distance, Bagolini striated glasses test (BSGs) and Worth four-dot lights test (WFDT).
    RESULTS: Mean age at evaluation was of 47,2 ± 16.07 years. Twenty-two (88%) out of 25 patients had a PEO disease, while three (12%) of them a Kearn-Sayre syndrome (KSS). Ocular motility impairment was found in 92% of the population. Fifteen patients (60%) didn't complain of double vision in casual seeing condition despite some of them showed manifest strabismus both at far (53%) and at near (60%). A compensation sensorial mechanism, mainly suppression, was detected through sensory tests. The near and distance fusional capabilities in convergence and in divergence (CFAs and DFAs) were absent in 68 and 72% of the whole sample respectively. PEO manifests at an older age than KSS (p = 0.003), diplopia does not correlate with disease duration (p = 0.06) and no predictive factors for diplopia can be identified.
    CONCLUSIONS: A significant number of patients not complaining of double vision in casual seeing state showed manifest or latent/manifest strabismus at FAoD and NAoD. Most strabismic patients had a monocular suppression or alternate diplopia and suppression at sensory tests (BSGs and WFDT). The pathophysiology of these sensory adaptations in an adult visual system can only be hypothesized. A multidisciplinary approach is essential for proper clinical management and to analyze an understand clinical features pathogenesis.
    Keywords:  Mitochondrial diseases; Mitochondrial diseases diplopia; Mitochondrial diseases eyelid ptosis; Mitochondrial diseases strabismus; Neurological strabismus; Ophthalmological abnormalities in mitochondrial diseases
    DOI:  https://doi.org/10.1186/s12886-025-04194-6
  28. J Mol Neurosci. 2025 Oct 02. 75(4): 131
    Spinocerebellar Ataxia Type 1 (SCA1) Cell Models Display Widespread Mitochondrial and Extra-Nuclear Alterations.
    Dane Ford-Roshon, Madison Dudek, Ada Glynn, Abigale Glasman, Jaden York, Emily Lawrence, Donna Nguyen, Lindsay Shinn, Georgia Berry, Lily Kendall, Jennifer Bonner, Austin Ferro, Sarita Lagalwar.
      Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1's altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.
    Keywords:  Ataxin-1; Mitochondrial Dysfunction; Neurodegeneration; Spinocerebellar Ataxia Type 1
    DOI:  https://doi.org/10.1007/s12031-025-02425-5
  29. Genet Med. 2025 Oct 01. pii: S1098-3600(25)00242-4. [Epub ahead of print] 101595
    A recurrent missense variant in the PPIB gene encoding peptidylprolyl isomerase B underlies adult-onset autosomal dominant optic atrophy.
    Katharina Valentin, Monika Kustermann, Mona R Schneider, Haleh Aminfar, Kathrin Vollnhofer, Andreas Wedrich, Christoph Stapf, Martin Bertich, Markus Ritter, Theresa Mendrina, Daniel Valcanover, Walter Berger, Margret Eckhard, Andy Sombke, Stephanie V Lilja, Amina Paquay, Bernhard Rosensteiner, Iris Schmidt, Reginald E Bittner, Thomas P Georgi, Berthold Pemp, Wolfgang M Schmidt.
       PURPOSE: Hereditary optic atrophy (OA) represents one of the leading causes of blindness. A relatively large number of genes, many of which are implicated in mitochondrial function, are known to be involved in OA. For many affected individuals, however, a genetic cause still cannot be identified.
    METHODS: In large pedigree and additional families, exome sequencing (ES) was used to identify a genetic cause in individuals with so far genetically unresolved OA. Subsequently, mitochondrial function was studied in cultured dermal fibroblasts.
    RESULTS: ES revealed a heterozygous missense variant in PPIB [NM_000942.5:c.538C>T p.(Arg180Trp)], encoding peptidylprolyl isomerase B, which segregated with clinically isolated OA in 19 individuals from 9 families. PPIB-associated OA involves an insidious reduction in visual acuity, central scotoma and inner retinal layer thinning consistent with other autosomal dominant OAs. Age of symptom onset was mostly in adulthood (median: 36 years), and severity of clinical manifestation was variable. Patient-derived fibroblasts revealed altered mitochondrial morphology as well as subtle respiratory chain defects.
    CONCLUSIONS: The PPIB variant segregates with OA, which might be caused by compromised mitochondrial function. While future studies are needed to study the exact pathomechanistic role of PPIB, insights from this work broaden the knowledge of genes implicated in autosomal dominant OA.
    Keywords:  CYPB; PPIase B; inherited optic neuropathy; mitochondrial disorder; optic atrophy
    DOI:  https://doi.org/10.1016/j.gim.2025.101595
  30. Angew Chem Int Ed Engl. 2025 Sep 30. e202514980
    Engineering Artificial Mitochondria with Self-Amplifying Proton Generation for Autonomous Energy Supply and Metabolic Coupling in Artificial Cells.
    Fangqin Fu, Xuemei Hu, Shijia Tao, Yu Gao, Daniel Crespy, Katharina Landfester, Xiangzhao Mao, Shuai Jiang.
      A continuous and autonomous energy supply is essential for sustaining life-like biochemical processes in artificial cells. Although considerable efforts have been devoted to engineering artificial organelles that emulate mitochondrial energy conversion, the generation of a robust transmembrane proton gradient-essential for driving efficient ATP production-remains a major challenge. Here, we present a mitochondria-mimicking ATP nano-generator constructed through quantitative co-compartmentalization of glucose oxidase and catalase within silica nanocapsules. Enzymes are encapsulated in situ during the formation of core-shell nanocapsules, enabling precise loading, effective protection, and creation of a confined nanoscale reaction chamber that fosters catalytic synergy. Within this microenvironment, catalase rapidly decomposes H2O2 to generate O2, which is in turn utilized by glucose oxidase-thus establishing a self-reinforcing enzymatic cascade that amplifies proton production. After coating the enzyme-loaded nanocapsules with an ATPase-integrated liposome bilayer to construct the artificial mitochondrion, the resulting proton gradient across the membrane efficiently drives ATP synthase rotation, enabling high-yield ATP production. When integrated into giant unilamellar vesicles (GUVs) as synthetic cell models, this system supports autonomous nicotinamide adenine dinucleotide (NADH) biosynthesis and glucose-powered oxidative phosphorylation, mimicking key metabolic features of living mitochondria. This work establishes an effective and versatile platform for engineering energy-autonomous artificial living systems, advancing the state of the art of bottom-up synthetic biology.
    Keywords:  Bioenergy; Cascade reactions; Metabolic mimicry; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1002/anie.202514980
  31. Front Cell Dev Biol. 2025 ;13 1646072
    Mitochondrial fission process 1 protein: a comprehensive review of its core roles in mitochondrial dynamics, disease, and therapeutic targets.
    Qingzhi Ran, Chen Gao, Chunrong Xiang, Xuanhui He, Yongkang Zhang, Yin Zhang, Hengwen Chen.
      Mitochondrial fission process 1 (MTFP1) has emerged as a central regulator of mitochondrial dynamics, playing indispensable roles in maintaining organellar integrity, bioenergetic homeostasis, and stress adaptation - particularly in high-energy-demand tissues such as cardiac and skeletal muscle. Mounting evidence implicates MTFP1 dysfunction in the pathogenesis of diverse diseases including cardiovascular disorders, myopathies, and cancer. Beyond its canonical role in mediating mitochondrial fusion-fission balance, recent studies have unveiled MTFP1's multifaceted involvement in calcium signaling modulation, ROS metabolism, and mitochondria-ER communication networks, substantially expanding its functional repertoire in cellular physiology. The protein's pleiotropic effects stem from its ability to integrate metabolic status with organelle dynamics and quality control mechanisms. Particularly noteworthy is MTFP1's cell-type-specific regulation of the ROS-calcium axis, which appears critical for its differential impacts in disease states. These discoveries position MTFP1 as both a mechanistic linchpin connecting mitochondrial dynamics to cellular homeostasis and a promising but challenging therapeutic target requiring precise contextual modulation. Current research frontiers focus on elucidating tissue-specific regulatory mechanisms of MTFP1 activity, developing microenvironment-sensitive targeting strategies, and exploring its potential as a biomarker for mitochondrial dysfunction-related pathologies. This evolving understanding of MTFP1's integrative functions opens new avenues for developing precision therapies targeting mitochondrial dynamics in energy-metabolism-linked diseases.
    Keywords:  Mitochondria; Tumor; autophagy; cardiovascular disease; drug Targets; inflammation; mitochondrial fission process 1 protein
    DOI:  https://doi.org/10.3389/fcell.2025.1646072
  32. Sci Rep. 2025 Sep 30. 15(1): 33959
    Proteomic analysis of brain and spinal cord tissue reveals distinct immune and mitochondrial processes between human and mouse ALS models.
    Alanna G Spiteri, Joel R Steele, Han-Chung Lee, Haijian Zhang, Jiaqi Sun, Ralf B Schittenhelm, Chien-Hsiung Yu, Catriona McLean, Colin L Masters, Benjamin Goudey, Liang Jin, Yijun Pan.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the progressive loss of motor neurons in the brain and spine. More than 95% of cases are pathologically characterized by the cytoplasmic accumulation of hyperphosphorylated and ubiquitinated transactive response DNA-binding protein 43 (TDP-43). Multiple mouse models with TDP-43 accumulation have been developed, however, whether they recapitulate molecular features of ALS pathology is unclear. Given the lack of curative treatment for ALS, there is an urgent need to identify the precise biological processes contributing to disease pathogenesis for the development of effective therapeutic treatments. Thus, in this study we employed label-based untargeted proteomics to characterize the ALS proteome and related biological processes in the spinal cord and brain of TDP-43Q331K mice, a transgenic mouse model of ALS and the motor cortex and the cervical, thoracic, and lumbar spinal cord regions from humans. In humans, we observed highly overlapping responses across the four tissues examined, primarily related to the upregulation of immune processes and the downregulation of mitochondrial function. In contrast, TDP-43Q331K mice demonstrate a lack of enrichment for immune activation and the opposite regulation of mitochondrial processes. A meta-analysis of previously published mouse datasets identified the Ubqln2 knock-out mouse model as showing stronger parallels with our late-stage human ALS. Overall, this study provides in-depth analysis of the site-specific dysregulated proteomes and their associated functional processes across species. Thereby, identifying potential therapeutic targets while emphasizing the limitations of specific mouse models at certain timepoints in recapitulating ALS-related processes for future model development.
    Keywords:  Amyotrophic lateral sclerosis; Immune-mediated pathology; Mitochondrial dysfunction; Motor neurone disease; Neurodegeneration; TMT-proteomics
    DOI:  https://doi.org/10.1038/s41598-025-11466-0
  33. Mol Cell. 2025 Oct 02. pii: S1097-2765(25)00714-2. [Epub ahead of print]85(19): 3554-3561
    A needed nomenclature for nucleosomes.
    Michael-Christopher Keogh, Genevieve Almouzni, Andrew J Andrews, Karim-Jean Armache, Cheryl H Arrowsmith, Sung Hee Baek, Mark T Bedford, Emily Bernstein, Jacques Côté, Yael David, John M Denu, Beat Fierz, Benjamin A Garcia, Karen C Glass, Or Gozani, Kristian Helin, Steven Henikoff, Ole N Jensen, Steven Z Josefowicz, Neil L Kelleher, Tatiana G Kutateladze, Herbert H Lindner, Chao Lu, Karolin Luger, Parag Mallick, Catherine A Musselman, Tom W Muir, Ljiljana Paša-Tolić, Robert Schneider, Xiaobing Shi, Yang Shi, Simone Sidoli, Lloyd M Smith, Jessica K Tyler, Cynthia Wolberger, Jerry L Workman, Brian D Strahl, Nicolas L Young.
      Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform to describe the particular gathering of histones within an individual nucleosome. There is now a need to define specific forms of these entities in prose while providing space for experimental nuance. To this end, we introduce a nomenclature that can express discrete PTMs, proteoforms, nucleoforms, or situations where defined PTMs exist in an uncertain context. Though specifically designed for the chromatin field, adaptions of the framework could be used to describe-and thus dissect-how proteoforms are configured in functionally distinct complexes across biology.
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.029
  34. J Pediatr Endocrinol Metab. 2025 Sep 29.
    Pitfalls in the diagnosis of carnitine palmitoyltransferase 1 deficiency.
    Sarah C Grünert, Urs Berger, Friederike Hörster, Kathrin Schwarz, Eva Thimm, Ute Spiekerkoetter, Dorothea Haas, Anke Schumann.
       OBJECTIVES: Carnitine palmitoyltransferase 1 A (CPT1A) deficiency is an ultra-rare autosomal recessive disorder of the carnitine cycle caused by biallelic pathogenic variants in the CPT1A gene. It mainly presents with a hepatic phenotype and is a target disease of newborn screening programs worldwide. Disease-specific and diagnostic abnormalities of CPT1A deficiency comprise elevated concentrations of free carnitine as well as an elevated metabolite ratio [C0/(C16 + C18)] in blood, but the ideal sample material has been a matter of debate.
    METHODS: We present biochemical data of five CPT1A deficient patients, of whom four were diagnosed by newborn screening from dried blood spots.
    RESULTS: Our cases demonstrate that acylcarnitine profiles and especially concentrations of free carnitine can be normal in plasma in infants with CPT1AD at confirmation diagnosis after screening and during follow-up. Even the [C0/(C16 + C18)] ratio yielded normal results in some cases.
    CONCLUSIONS: Our data show, that dried blood is the preferred sample material for the diagnosis of CPT1A deficiency as it is superior to serum/plasma with respect to diagnostic sensitivity and reliability in quantification of the ratio [C0/(C16 + C18)]. CPT1A deficiency can be missed, if the analysis is only performed in serum or plasma, and confirmatory diagnostics in serum or plasma after screening can be false negative.
    Keywords:  CPT1A; acylcarnitines; carnitine palmitoyltransferase 1A deficiency; dried blood spots; free carnitine; newborn screening
    DOI:  https://doi.org/10.1515/jpem-2025-0382
  35. Clin Genet. 2025 Sep 29.
    Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM, ACADVL and SLC22A5 Genes.
    Irene Hidalgo Mayoral, Amanda Herranz Cecilia, Carmen Rodríguez-Jiménez, Ana Carazo Álvarez, Ana Bergua Martínez, José David Andrade Guerrero, Ana Moráis López, Sonia Rodríguez-Nóvoa.
      In this study, we aimed to assess clinical, laboratory and molecular features of newborns with clinical suspicion for systemic primary carnitine deficiency (CUD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). The implementation of newborn screening programs for fatty acid β-oxidation disorders (FAODs) has changed the natural course of these diseases, facilitating the initiation of preventive or therapeutic measures for affected newborns shortly after birth. This study included 94 newborns who were admitted between 2016 and 2023 because of biochemical signs of CUD, MCADD and VLCADD, and provided clinical, biochemical and genotypic data. Definitive molecular diagnosis confirmed that 16/94 newborns (17%) were true positives of the NBS, and 17 novel variants were detected in SLC22A5, ACADM and ACADVL genes. We assessed the clinical evolution of patients over time. This study expands the genotypic spectrum of SLC22A5, ACADM and ACADVL and highlights the role of genetics in identifying and correctly characterising FAODs.
    Keywords:  CUD; FAODs; MCADD; NBS; VLCADD; newborn screening
    DOI:  https://doi.org/10.1111/cge.70083
  36. Nat Commun. 2025 Sep 30. 16(1): 8693
    Geometrically-engineered human motor assembloids-on-a-chip for neuromuscular interaction readout and hypoxia-driven disease modeling.
    Weihua Zhang, Liming Yu, Jie Pan, Jiajia Deng, Xianqin Tong, Bingjiao Zhao, Wen Liu, Liangyan Sun, Menghan Zhang, Xinxin Han, Tingjiao Liu, Yun Lu, Jiao Li, Yuehua Liu.
      Precision medicine leverages stem cell-derived models to dissect complex interactions underlying disease-driven neuromuscular damage. However, such reductionist models form stochastic structures without external guidance, while available engineering solutions remain intricate. Here, simplified surface modification engineering is used to render spatially patterned human motor assembloids-on-a-chip by geometric confinement. The anisotropic architecture of skeletal muscle organoids (hSkM) can be conferred solely by localized mechanobiological cues within this predefined device without aligned scaffolds or adjuncts. The hSkM-orchestrated coupling of motor neuron spheroids (hMNS) promotes synergistic neuromuscular development. Furthermore, integration of optogenetic and microelectrode array mapping enables visualization of functional patterning in assembloids. Applied to oxygen deprivation model, hSkM exhibits structural anomalies, fatigable muscle remodeling and dysfunction, recapitulating muscle pathologies in intermittent hypoxia (IH)-associated respiratory disorders. Electrical activity mapping reveals the heterogeneity in neuromuscular responses to IH, indicating the neuroregulatory etiology of muscle dysfunction. Finally, we identify mitochondrial bioenergetic imbalance as a key IH target, proposing evaluation of NAD+ salvage pathway-targeting agents. Our findings provide an accessible platform with translational potential for neuromuscular physiopathology research.
    DOI:  https://doi.org/10.1038/s41467-025-63736-0
  37. Eur J Hum Genet. 2025 Oct 03.
    Evaluating DNA methylation episignatures as a first-tier diagnostic test in individuals with suspected genetic disorders.
    Tinatin Tkemladze, Christopher Campbell, Kakha Bregvadze, Eka Kvaratskhelia, Elene Abzianidze, Leigh Demain, Sarah Jenkinson, Sarah Hilton, Michael Levy, Jennifer Kerkhof, David Gokhale, Bekim Sadikovic, Siddharth Banka.
      DNA methylation (DNAm) episignature analysis is an emerging tool for diagnosing individuals with neurodevelopmental disorders, congenital anomalies, and growth disorders. We evaluated its clinical utility as a first-tier test in 62 individuals without prior molecular testing. DNAm arrays identified a diagnosis in 30.6% (19/62) of cases. The positivity rate was highest for Fragile X syndrome (100%, 5/5), followed by syndromic disorders (44%, 8/18) and imprinting disorders (25%, 6/24), including Silver-Russell, Beckwith-Wiedemann, and Prader-Willi syndromes. No diagnoses were made in 15 individuals with non-syndromic neurodevelopmental disorders. Alternative diagnoses were identified in 4.8% (3/62) of cases. These findings suggest that DNAm arrays can serve as an effective first-tier diagnostic tool, particularly for syndromic and imprinting disorders, with potential to improve diagnostic efficiency and reduce reliance on sequential genetic testing. While these findings support the use of DNAm arrays as an effective first-tier tool in selected populations, larger, unselected cohort studies are needed to validate its generalizability.
    DOI:  https://doi.org/10.1038/s41431-025-01939-1
  38. Nat Protoc. 2025 Sep 30.
    Spatially resolved in situ profiling of mRNA life cycle at transcriptome scale in intact cells and tissues using STARmap PLUS, RIBOmap and TEMPOmap.
    Jingyi Ren, Hu Zeng, Jiahao Huang, Jiakun Tian, Morgan Wu, Hailing Shi, Xin Sui, Connie Kangni Wang, Haowen Zhou, Zefang Tang, Shuchen Luo, Xiao Wang.
      Controlled gene expression programs have a crucial role in shaping cellular functions and activities. At the core of this process lies the RNA life cycle, ensuring protein products are synthesized in the right place at the right time. Here we detail an integrated protocol for imaging-based highly multiplexed in situ profiling of spatial transcriptome using antibody-based protein comapping (STARmap PLUS), spatial translatome mapping (RIBOmap) and spatiotemporal transcriptome mapping (TEMPOmap). These methods selectively convert targeted RNAs, ribosome-bound mRNAs or metabolically labeled RNAs to DNA amplicons with gene-unique barcodes, which are read out through in situ sequencing under a confocal microscope. Compared with other methods, they provide the analytical capacity to track the spatial and temporal dynamics of thousands of RNA species in intact cells and tissues. Our protocol can be readily performed in laboratories experienced in working with RNA and equipped with confocal microscopy instruments. The wet lab experiments in preparing the amplicon library take 2-3 d, followed by variable sequencing times depending on the sample size and target gene number. The spatially resolved single-cell profiles enable downstream analysis, including cell type classification, cell cycle identification and determination of RNA life cycle kinetic parameters through computational analysis guided by the established tutorials. This spatial omics toolkit will help users to better understand spatial and temporal RNA dynamics in heterogeneous cells and tissues.
    DOI:  https://doi.org/10.1038/s41596-025-01248-3
  39. Orphanet J Rare Dis. 2025 Oct 02. 20(1): 498
    Somewhere to go: a position paper on addressing gaps in transition care for adults with childhood-onset rare diseases.
    Laura L Tosi, Tracy S Hart, Gabriela Beug, Erika Carter, Eleanor M Perfetto.
      Adults with childhood-onset rare disease face many challenges when transitioning from pediatric services to adult care. While they often received specialized pediatric care, the adult healthcare system provides few resources for those whose rare disease began in childhood. Many adult care providers are hesitant to take on adults with rare disease and may shunt them elsewhere. Treatment recommendations are evolving rapidly, making it difficult for any clinician to stay up to date, and patients with rare disease often have special needs that must be addressed by multiple specialists at once. These young adults are often faced with "nowhere to go" for care.A pressing question is: What can be done now to help adult patients with rare diseases gain access to the care they need. In response, a patient-community-driven, solution-oriented conference was held, entitled, "Somewhere to Go for Adults with Childhood-Onset Rare Diseases: A Conversation About How We Can Fill Gaps in Care." The purpose was to bring the rare-disease community together to explore action steps that could be taken in the next two to three years to address the growing, national care crisis for adults with rare diseases transitioning from pediatric to adult care. This position paper provides an overview of the key topics discussed and summarizes the 21 prioritized, actionable recommendations produced.
    Keywords:  Adult rare disease care; Childhood-onset rare disease; Transition of care
    DOI:  https://doi.org/10.1186/s13023-025-03973-0
  40. Neurology. 2025 Nov 11. 105(9): e214210
    Teaching NeuroImage: Multiple Symmetric Lipomatosis as a Manifestation of Mitochondrial Cytopathy.
    Riya Sharma, Siddharth Chand, Ravish Padda, Ritu Shree, Debajyoti Chatterjee, Manoj Kumar Goyal, Manish Modi.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000214210
  41. bioRxiv. 2025 Sep 22. pii: 2025.09.22.677815. [Epub ahead of print]
    DDHD2 possesses both lipase and transacylase capacities that remodel triglyceride acyl chains.
    Lingshuang Wu, Yong Mi Choi, Mohyeddine Omrane, Jiyao Chai, Shujuan Gao, Abdou Rachid Thiam, Daniel Canals, Michael V Airola.
      Hereditary spastic paraplegia subtype SPG54 is a genetic neurological disorder caused by mutations in the DDHD2 gene. Excessive lipid droplet accumulation is observed in the brains of SPG54 patients and DDHD2 knockout mice, consistent with DDHD2's reported neutral lipase activity. Here, we find recombinant human DDHD2 preferentially hydrolyzes diacylglycerol (DAG) over phospholipids, with a slight preference for DAG over triacylglycerol (TAG). DDHD2 also exhibits transacylase activity, which enables transfer of acyl chains from triacylglycerols to diacylglycerols and monoacylglycerols to remodel the acyl chains of triglycerides. A predicted hydrophobic amphipathic helix on DDHD2 is essential for lipid droplet binding in vitro and in cells, and its lack reduces the enzymatic activity and triglyceride acyl chain remodeling. Adipose triglyceride lipase (ATGL), but not hormone sensitive lipase (HSL), also has transacylation activity and can remodel triglyceride acyl chains, but to a lesser extent than DDHD2. Taken together, this provides evidence that DDHD2 is a neutral lipid lipase and transacylase whose broad specificity enables triglyceride acyl-chain remodeling.
    SIGNIFICANCE STATEMENT: Triglycerides (TAGs), the primary form of long-term energy storage, have acyl chain compositions crucial for diverse cellular processes. Lipases typically hydrolyze TAGs into free fatty acids. Here, we reveal a novel function for the neutral lipid lipase DDHD2: a transacylase activity. Instead of releasing fatty acids, DDHD2 transfers them between neutral lipids, altering TAG acyl chain composition. This transacylation requires the unique oil environment of lipid droplets (LDs), which excludes water from DDHD2's lipolytic active site, favoring transacylation over hydrolysis. DDHD2's lipase and transacylase activities enable TAG acyl-chain remodeling, demonstrating the possibility that a single enzyme can catalyze TAG cycling. This finding has implications for understanding lipid metabolism, LD dynamics, and specific motor neuron diseases implicating DDHD2.
    DOI:  https://doi.org/10.1101/2025.09.22.677815
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