bims-curels 2025-05-04 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–05–04
25 papers selected by
Cure Mito Foundation

Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.
Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.
Ramping up mitochondrial DNA replication.
Spectrum of clinical neuroimaging in mitochondrial disorders: a neuroanatomical approach.
Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.
The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.
A case of acute promyelocytic leukemia complicated by mitochondrial disease.
Incorporating Patient Input into the Target Product Profile.
The role of gut microbiota-mitochondria crosstalk in neurodegeneration: Underlying mechanisms and potential therapies.
Genetic diseases.
Successful application of vagus nerve stimulation in super refractory status epilepticus associated with MERRF syndrome.
The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.
Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.
Therapeutic Potential of Enzymes, Neurosteroids, and Synthetic Steroids in Neurodegenerative Disorders: A Critical Review.
Qualitative analysis of the needs of parents of children with rare genetic diseases, following their diagnosis obtained by whole-exome sequencing.
Communicating Numeric Risk Information to Patients.
Mitochondria - the CEO of the cell.
Advances in research on mitochondrial dysfunction in neurodegenerative diseases.
Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.
Antisense Oligonucleotides: A Promising Advancement in Neurodegenerative Disease Treatment.
Crossed Cerebellar Diaschisis in a Patient with MELAS Syndrome: A Case Report.
Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
Patient passports have the potential to improve patient care.
Haplogroup Structure and Genetic Variation Analyses of Mitochondrial Genome SNPs in the Iranian Population.

Genes Dis. 2025 Jul;12(4): 101437

Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.

Ye Hong, Ying Song, Wenjun Wang, Jinghui Shi, Xi Chen.

  Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.

Keywords:  Base editor; CRISPR-Cas9; Mitochondrial DNA; Neurodegenerative diseases; mitoTALENs; mitoZFNs

DOI:  https://doi.org/10.1016/j.gendis.2024.101437
Am J Hum Genet. 2025 Apr 23. pii: S0002-9297(25)00144-2. [Epub ahead of print]

Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience.

Solve-RD Consortium

  The diagnosis of mitochondrial DNA (mtDNA) diseases remains challenging with next-generation sequencing, where bioinformatic analysis is usually more focused on the nuclear genome. We developed a workflow for the evaluation of mtDNA diseases and applied it in a large European rare disease cohort (Solve-RD). A semi-automated bioinformatic pipeline with MToolBox was used to filter the unsolved Solve-RD cohort for rare mtDNA variants after validating this pipeline on exome datasets of 42 individuals previously diagnosed with mtDNA variants. Variants were filtered based on blood heteroplasmy levels (≥1%) and reported association with disease. Overall, 10,157 exome and genome datasets from 9,923 affected individuals from 9,483 families within Solve-RD met the quality inclusion criteria. 136 mtDNA variants in 135 undiagnosed individuals were prioritized using the filtering approach. A focused MitoPhen-based phenotype similarity scoring method was tested in a separate genetically diagnosed "phenotype test cohort" consisting of nuclear gene and mtDNA diseases using a receiving operator characteristic evaluation. We applied the MitoPhen-based phenotype similarity score of >0.3, which was highly sensitive for detecting mtDNA diseases in the phenotype test cohort, to the filtered cohort of 135 undiagnosed individuals. This aided the prioritization of 34 out of 37 (92%) individuals who received confirmed and likely causative mtDNA disease diagnoses. The phenotypic evaluation was limited by the quality of input data in some individuals. The overall pipeline led to an additional diagnostic yield of 0.4% in a cohort where mitochondrial disease was not initially suspected. This highlights the value of our mtDNA analysis pipeline in diverse datasets.

Keywords:  Solve-RD; bioinformatics; mitochondrial DNA; phenotype similarity; reanalysis

DOI:  https://doi.org/10.1016/j.ajhg.2025.04.003
Nat Rev Drug Discov. 2025 May 02.

Ramping up mitochondrial DNA replication.

Katie Kingwell.

DOI: https://doi.org/10.1038/d41573-025-00079-x
Pediatr Radiol. 2025 May 02.

Spectrum of clinical neuroimaging in mitochondrial disorders: a neuroanatomical approach.

Kate Kielty, John Collyer, Krrithvi Dharini Ganesh, Srikala Narayanan, Deepa S Rajan.

  Mitochondrial disorders are a highly heterogeneous group of genetic diseases that impact pathways associated with the structure and function of the mitochondrion. Clinical presentations of mitochondrial disorders include a wide range of onset, progression, and spectrum of neurological symptoms - ranging from episodic, focal neurological deficits to gradual onset of developmental delays, sensorineural hearing loss, visual impairment, or ataxia. This variability provides clinicians with a diagnostic challenge in identifying suspicion of a mitochondrial disorder and prioritizing specific mitochondrial disorders within their differential. While next-generation sequencing of both the nuclear and mitochondrial genomes has aided identification of mitochondrial disorders, testing results are typically not available for weeks to months, and CSF and biochemical studies indicating possible mitochondrial disorder, such as elevated lactate, are nonspecific in differentiating between mitochondrial disorders and other neurogenetic diseases. Neuroimaging can serve as an early tool to help identify specific mitochondrial disorders; however, there are additional variability and overlap between disorders and other non-mitochondrial diseases. This review provides a framework in narrowing the mitochondrial differential by neuroanatomical localization on neuroimaging studies. We will highlight established neuroimaging patterns associated with mitochondrial disorders, review the role of MRS, and discuss the alternative non-mitochondrial etiologies associated with these findings.

Keywords:  MRI; Metabolic disorders; Mitochondrial disorders; Neuroanatomy; Neurogenetics; Neuroimaging

DOI:  https://doi.org/10.1007/s00247-025-06252-z
Curr Stem Cell Res Ther. 2025 Apr 25.

Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential.

Jingyi Chen, Zhilang Xie, Huayin Zhou, Yingxin Ou, Wenwen Tan, Aizhen Zhang, Yuying Li, Xingliang Fan.

  Mesenchymal stem cells (MSCs) hold transformative potential in translational medicine due to their versatile differentiation abilities and regenerative properties. Notably, MSCs can transfer mitochondria to unrelated cells through intercellular mitochondrial transfer, offering a groundbreaking approach to halting the progression of mitochondrial diseases and restoring function to cells compromised by mitochondrial dysfunction. Although MSC mitochondrial transfer has demonstrated significant therapeutic promise across a range of diseases, its application in clinical settings remains largely unexplored. This review delves into the novel mechanisms by which MSCs execute mitochondrial transfer, highlighting its profound impact on cellular metabolism, immune modulation, and tissue regeneration. We provide an in-depth analysis of the therapeutic potential of MSC mitochondrial transfer, particularly in treating mitochondrial dysfunction-related diseases and advancing tissue repair strategies. Additionally, we propose innovative considerations for optimizing MSC mitochondrial transfer in clinical trials, emphasizing its potential to reshape the landscape of regenerative medicine and therapeutic interventions.

Keywords:  Mesenchymal stem cells; immunomodulation; mitochondrial transfer; oxidative stress; therapeutic potential.

DOI:  https://doi.org/10.2174/011574888X362739250416153254
Hum Mol Genet. 2025 Apr 29. pii: ddaf061. [Epub ahead of print]

The copper ionophore disulfiram improves mitochondrial function in various yeast and human cellular models of mitochondrial diseases.

Claire Almyre, Nolwenn Bounaix, François Godard, Olivier R Baris, Anne-Louise Cayer, Elodie Sardin, Marine Bouhier, Anaïs Hoarau, Laetitia Dard, Jérémy Richard, Vanessa Bergeron, Aurélie Renaud, Nadege Loaëc, Naïg Gueguen, Valérie Desquiret-Dumas, Bénédicte Lelievre, Aurore Inisan, Cristina Panozzo, Genevève Dujardin, Marc Blondel, Agnes Rötig, Véronique Paquis-Flucklinger, Stéphane Azoulay, Nathalie Bonnefoy, Carole H Sellem, Agnès Delahodde, Vincent Procaccio, Déborah Tribouillard-Tanvier.

  The copper ionophore disulfiram (DSF) is commonly used to treat chronic alcoholism and has potential anti-cancer activity. Using a yeast-based screening assay of FDA-approved compounds, DSF was herein identified for its ability to improve oxidative phosphorylation-dependent growth of various yeast models of mitochondrial diseases caused by a wide range of defects in ATP synthase, complexes III and IV, cardiolipin remodeling, maintenance and translation of the mitochondrial genome. This compound also showed beneficial effects in cells derived from patients suffering from Barth or MELAS syndromes, two mitochondrial diseases associated respectively with a lack in cardiolipin remodeling and protein synthesis inside the organelle. We provide evidence that the rescuing activity of DSF results from its ability to transport copper ions across biological membranes. Indeed, other copper ionophores (pyrithione and elesclomol) and supplementation of the growth media with copper ions had also beneficial effects in yeast and human cells with dysfunctional mitochondria. Our data suggest that the copper-dependent rescuing activity in these cells results from a better capacity to assemble cytochrome c oxidase. Altogether, our findings hold promise for the development of new therapeutic strategies for mitochondrial disorders.

Keywords:  Mitochondrial diseases; copper; disulfiram; drug repositioning; oxidative phosphorylation

DOI:  https://doi.org/10.1093/hmg/ddaf061
Int J Hematol. 2025 May 01.

A case of acute promyelocytic leukemia complicated by mitochondrial disease.

Yukari Sakurai, Masakatsu Yanagimachi, Mieko Ito, Ayana Hirose, Naoyuki Miyagawa, Dai Keino, Tomoko Yokosuka, Fuminori Iwasaki, Satoshi Hamanoue, Masae Shiomi, Shoko Goto, Tomohide Goto, Hiroaki Goto.

  A 15-year-old boy with congenital mitochondrial disease was diagnosed with acute promyelocytic leukemia. He was treated with all-trans retinoic acid, and his anthracycline dose was reduced in response to his underlying condition. He successfully achieved molecular remission and maintained this state for 4 years. In vitro drug sensitivity testing in peripheral mononuclear cells suggests that samples from patients in remission show higher sensitivity to various anticancer drugs than samples from healthy volunteers. Reduced-dose chemotherapy could be a valid treatment option for patients with mitochondrial diseases because exposure to elevated oxidative stress may contribute to increased drug sensitivity in these patients.

Keywords:  Acute promyelocytic leukemia; Anthracycline; Mitochondrial disease; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12185-025-03992-4
Ther Innov Regul Sci. 2025 Apr 25.

Incorporating Patient Input into the Target Product Profile.

Jean-Noel Talabardon, Janet E Church, Masanori Okuse, Michaela Dinboeck, Sheila Dickinson, Simon Messner, Michael Boisclair, Jean-Pierre Malkowski.

  Target product profiles (TPP) are summaries of characteristics which drug developers expect to be necessary for a product to meet patients' needs, receive regulatory and payer approval, and differ from existing treatment options. As the experts on their own disease, patients bring invaluable perspectives to drug development, which cannot be obtained by other means. This communication reports on the development of a systematic guidance framework for a patient-focused, standardized TPP. The guidance was developed in a long-term iterative process, with crucial aspects reviewed and validated with the patient community. Five focus areas of a TPP were identified where patient perspectives are fundamental: target population, unmet need, dosage frequency and route of administration, efficacy endpoints, and acceptability of benefit/risk profile trade-offs. A guiding principle should be to incorporate patient perspectives in a systematic process starting as early as possible. A number of tools are available for obtaining patient perspectives, e.g., desk research, patient advisory boards/patient councils/online bulletin boards, focus groups with patients/caregivers, and/or in-depth interviews. When discussing the proposed process with patient representatives, they identified several key requirements for the interaction between R&D organizations and patient representatives. These include the use of clear language, respect for patients, engagement with patient experts, provision of adequate context and background information. We further discuss the relative importance of integrating patient perspectives into the different focus areas and touch upon the potential benefits to patient organizations from adapting these concepts and processes to enhance their voices in drug development.

Keywords:  Patient engagement; Patient input; TPP; Target product profile

DOI:  https://doi.org/10.1007/s43441-025-00783-1
Neural Regen Res. 2025 Apr 29.

The role of gut microbiota-mitochondria crosstalk in neurodegeneration: Underlying mechanisms and potential therapies.

Tianjuan Ju, Yaoyuan Zhang, Lipeng Liu, Xitong Zhao, Xinwei Li, Changfeng Liu, Shukai Sun, Li-An Wu.

   ABSTRACT: Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis, which refers to the crosstalk between the gut and the central nervous system. More importantly, mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain. Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases. Mitochondria are essential for meeting the host's substantial neuronal metabolic demands, maintaining excitability, and facilitating synaptic transmission. Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases. Therefore, this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration, as well as the existing potential therapeutic strategies for neurodegenerative disorders. These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases, and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases. However, this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases, such as Huntington's disease and Multiple sclerosis, and the potential therapeutic strategies were translated into clinical trials, which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; gut microbiota; gut-brain axis; microbiota-mitochondria crosstalk; neurodegenerative diseases; neuroinflammation; probiotic; short chain fatty acid

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01419
Clin Chem Lab Med. 2025 May 26. 63(s1): s1285-s1341

Genetic diseases.

DOI: https://doi.org/10.1515/cclm-2025-8047
Epilepsy Behav Rep. 2025 Jun;30 100769

Successful application of vagus nerve stimulation in super refractory status epilepticus associated with MERRF syndrome.

Leyla Baysal, Sabrina Jobi, Simone Zimmermann, Ann-Kristin Helmers, Nils Gerd Margraf.

  Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a rare mitochondrial disorder marked by myoclonus, ataxia, cognitive impairment, myopathy, and sensorineural hearing loss. Seizures in MERRF syndrome are often resistant to standard antiseizure medication. We present a unique case of an adult patient with MERRF syndrome, caused by the m.8344A > G point mutation, who developed super-refractory status epilepticus (SRSE), successfully managed by the initiation and rapid escalation of vagus nerve stimulation (VNS) therapy. Over a two-year follow-up period, the VNS therapy enabled a long-term control of generalized tonic-clonic seizures. A further status epilepticus has not yet occurred. VNS may therefore be a promising therapeutic option for managing SRSE in patients with mitochondrial epilepsy syndromes.

Keywords:  MERRF syndrome; Mitochondrial disease; Super-refractory status epilepticus; Vagus nerve stimulation

DOI:  https://doi.org/10.1016/j.ebr.2025.100769
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 25. pii: S0925-4439(25)00221-2. [Epub ahead of print] 167873

The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.

Luciano Willemse, Karin Terburgh, Roan Louw.

   INTRODUCTION: Leigh syndrome is often caused by Ndufs4 mutations. The Ndufs4 knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in Ndufs4 KO mice.
METHODS: Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome.
RESULTS: The HFD significantly extended lifespan and improved clasping behaviour in Ndufs4 KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming.
CONCLUSION: Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.

Keywords:  Flow cytometry; Ketogenic diet; Lipidomics; Metabolomics; Mitochondrial disease; Polyunsaturated fatty acids; mTOR

DOI:  https://doi.org/10.1016/j.bbadis.2025.167873
EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

  Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI:  https://doi.org/10.1038/s44319-025-00459-9
J Clin Med. 2025 Apr 08. pii: 2537. [Epub ahead of print]14(8):

Clinical Ophthalmic Outcomes and Impact of Single Large-Scale Mitochondrial DNA Deletions.

Michael Otakhor Erhunmwunse, Pushpa Raj Joshi.

  Introduction/Objectives: Chronic progressive external ophthalmoplegia (CPEO) is commonly associated with mtDNA deletions. Multiple deletions result mostly due to nuclear DNA defects that lead to an autosomal mode of inheritance, whereas single mtDNA deletions are mostly sporadic events with low inheritance risk. The study focused on assessing the clinical ophthalmic outcomes and their effects on patients with mitochondrial DNA disorders. Methods: A retrospective analysis of clinical characteristics in a cohort of CPEO patients (n = 36; 11 males, 25 females; mean age of onset: 41.2 years (±SD)) was performed. The underlying genetic defects, as well as histological features and their correlation with the clinical features, were evaluated. Results: Ptosis (56% of patients) was a frequently identified clinical symptom. Single mtDNA deletions were reported in all patients, and the 'common' 4977 bp deletion (CD) was detected in 11 patients (30.6%). The incidence of the common deletion was higher (36.36%) in older patients (≥51 years) as compared to younger patients (18.18%). The mean age of onset in patients harboring CD was 27 years (±11.9). Furthermore, a tendency to increase the frequency of COX-deficient fibers with increasing age was observed in patients harboring the CD. Conclusions: The present study shows that CD is typically associated with elderly patients with CPEO. Moreover, ptosis and the presence of a single deletion in patients with mitochondrialopathy seem to be preliminary diagnostic criteria.

Keywords:  CPEO; common deletion (CD); mitochondrial DNA; ptosis

DOI:  https://doi.org/10.3390/jcm14082537
J Steroid Biochem Mol Biol. 2025 Apr 25. pii: S0960-0760(25)00094-9. [Epub ahead of print] 106766

Therapeutic Potential of Enzymes, Neurosteroids, and Synthetic Steroids in Neurodegenerative Disorders: A Critical Review.

Refik Servi, Ramazan Fazıl Akkoç, Feyza Aksu, Süleyman Servi.

  Neurodegenerative disorders present a significant challenge to healthcare systems, mainly due to the limited availability of effective treatment options to halt or reverse disease progression. Endogenous steroids synthesized in the central nervous system, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG), and allopregnanolone (ALLO), have been identified as potential therapeutic agents for neurodegenerative diseases. Neurosteroids such as ALLO, DHEA, and PROG, as well as their synthetic analogs like Ganaxolene, Fluasterone, and Olexoxime, offer promising effects for conditions such as Alzheimer's disease (AD) and depression. Moreover, Brexanolone and Ganaxolone are synthetic steroids approved for the treatment of postpartum depression and epilepsy, respectively. Neurosteroids such as ALLO are crucial in modulating GABAergic neurotransmission and reducing neuroinflammation. These compounds enhance the activity of GABA-A receptors, leading to increased inhibitory signaling in the brain, which can help regulate mood, cognition, and neuroprotection. Small clinical trials and observational studies indicate that ALLO may have cognitive benefits, but no large-scale, definitive meta-analysis confirms a 20% improvement in AD patients. Mitochondrial dysfunction plays a vital role in the pathogenesis of numerous neurological diseases due to the high-energy demand and sensitivity of neurons to oxidative stress. Reduced mitochondrial function leads to amyloid-beta plaques and tau tangles accumulation in AD. In Parkinson's disease (PD), mitochondrial dysfunction resulting from the PINK1 or Parkin genes leads to energy deficiencies and the accumulation of toxic byproducts. Mutations in genes such as SOD1, C9orf72, and TDP-43 have been associated with mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS). Moreover, studies on these neurodegenerative diseases suggest that inflammation is not merely a consequence of neurodegeneration but is also an essential factor in this process. Many neurological disorders involve multifaceted interactions between genetics, the environment, and immune responses, making it difficult to pinpoint their exact causes. Future research aims to overcome these hurdles through genetic advances, regenerative medicine, and personalized therapies. Cutting-edge technologies such as artificial intelligence and high-throughput screening are expected to accelerate drug discovery and improve diagnostic accuracy. Increasing collaboration between interdisciplinary fields such as bioinformatics, neuroscience, and immunology will lead to innovative treatment strategies. This comprehensive review discusses the therapeutic effects of enzymes, neurosteroids, and synthetic steroids in different neurodegenerative diseases, particularly AD, PD, ALS, and MS. Potential challenges in the therapeutic use of neurosteroids, such as the limited bioavailability and off-target effects of synthetic steroids, are also discussed, and an up-to-date and comprehensive review of the impact of these steroids on neurodegenerative disorders is presented.

Keywords:  Allopregnanolone; Alzheimer's disease; Anti-inflammatory effects; Dehydroepiandrosterone; GABAergic signaling; Mitochondrial dysfunction; Parkinson's disease; Synthetic steroids

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106766
J Genet Couns. 2025 Jun;34(3): e70015

Qualitative analysis of the needs of parents of children with rare genetic diseases, following their diagnosis obtained by whole-exome sequencing.

Mii Takatsuka, Akira Inaba, Akiko Yoshida, Sayoko Haruyama, Takahito Wada, Shinji Kosugi.

  In recent years, an increasing number of affected children have been diagnosed through whole-exome sequencing (WES); however, it remains unclear whether the problems faced by the patients' parents during the undiagnosed period were resolved. This exploratory qualitative study aimed to clarify the needs of the parents of children who have been diagnosed with rare genetic diseases and determine the factors that may help provide the environment necessary for the family to understand and accept the symptoms and characteristics associated with the disease and live with their affected child. Semi-structured interviews were conducted with the parents of children (less than 18 years old) who participated in a research project, namely the Initiative on Undiagnosed and Rare Diseases (IRUD), at Kyoto University Hospital between November 2016 and December 2021. A reflective thematic analysis generated three themes: the benefits of diagnosis from the perspective of parents, the challenges to be solved after diagnosis, and the significance and issues of revealing genetic information. The results showed that the diagnoses provided psychological satisfaction for the parents. However, diagnosis of a hereditary and rare disease can lead to social and medical isolation, and it was necessary to improve the environment around the affected children's families, mainly by taking advantage of the IRUD research system. The analysis indicated the need for psychological support, which can be provided by the clinical genetic department, the need for a follow-up system in collaboration with various clinical departments, and the need to improve the general public's understanding of human genetics.

Keywords:  a qualitative study; comprehensive genetic test; genetic counseling; parents; pediatrics; rare genetic diseases; whole‐exome sequencing

DOI:  https://doi.org/10.1002/jgc4.70015
J Gen Intern Med. 2025 Apr 29.

Communicating Numeric Risk Information to Patients.

Ellen Peters, Paul K J Han, Clara N Lee.

  Risk information is increasingly available to health care providers and patients thanks to a growing body of health outcomes research and clinical prediction models. Meanwhile, communicating such information is encouraged for a variety of reasons. Yet clinicians often struggle to communicate risk information-or forego the task altogether due to various challenges. The challenges are real, and this paper briefly discusses six of them: (1) Clinician reliance on verbal risk descriptions, (2) Low patient numeracy; (3) Lack of meaningful numeric evidence; (4) Patient use of heuristics; (5) Uncertain risk information; and (6) The curse of knowledge. Specific strategies exist for clinicians, though, to overcome these complex challenges. In the paper, we present evidence-based best practices with examples of what clinicians can do to effectively communicate risk information to their patients (and what they should not do). The best practices include communicating with numbers, not only words; decreasing cognitive effort for patients; providing the meaning of numeric risk data important to decisions; acknowledging uncertainty; and testing communication with patients through teach-back techniques. We conclude by recommending that clinicians integrate these strategies into their existing scripts for patient encounters.

Keywords:  numeracy; patient communication; risk communication; shared decision-making

DOI:  https://doi.org/10.1007/s11606-025-09520-8
J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):

Mitochondria - the CEO of the cell.

Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.

  As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.

Keywords:  Mitochondria; Organelle; mtDNA

DOI:  https://doi.org/10.1242/jcs.263403
J Neurol. 2025 Apr 28. 272(5): 364

Advances in research on mitochondrial dysfunction in neurodegenerative diseases.

Yao Zhang, Xiao-Wen Li, Yuan Zhang, Xing Li.

  Given the high energy demand of the nervous system, mitochondrial dysfunction is a key factor in the pathogenesis of neurodegenerative diseases. Thus, a comprehensive understanding of its mechanisms and potential therapeutic targets is essential. This review discusses the roles of mitochondrial oxidative stress, mitochondrial dynamics alterations, and mtDNA damage in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). In addition, it summarizes the contributions of novel technological approaches in detecting mitochondrial dysfunction, which assist in disease diagnosis. We also emphasize emerging therapeutic strategies and drugs aimed at enhancing mitochondrial quality control and reducing oxidative stress, thereby laying the groundwork for innovative therapeutic approaches in neurodegenerative disease treatment.

Keywords:  Detection technology; Mitochondrial dysfunction; Neurodegenerative diseases; Therapeutic targets

DOI:  https://doi.org/10.1007/s00415-025-13101-4
Theranostics. 2025 ;15(11): 5499-5517

Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.

Fei Peng, Xiaoniao Chen, Lingling Wu, Jiayi He, Zongjin Li, Quan Hong, Qiang Zhao, Meng Qian, Xu Wang, Wanjun Shen, Tingting Qi, Yiyu Huang, Guangyan Cai, Chuyue Zhang, Xiangmei Chen.

  Background: The disruption of mitochondrial homeostasis in acute kidney injury (AKI) is an important factor that drives persistent renal dysfunction. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great therapeutic potential in AKI, but insufficient specificity of targeting the impaired mitochondrial function. Herein, we developed an engineered nitric oxide (NO)-primed MSC-EVs (pEVs) to restore mitochondrial homeostasis for AKI therapy. Methods: A cisplatin-induced AKI model was established to investigate the therapeutic effects of MSC-EVs. Proteomic and Western blot analyses compared mitochondrial cargos and functional assays included mitochondrial complex I activity and Adenosine triphosphate (ATP) quantification. Mitochondrial transfer was tracked using flow cytometry and confocal imaging. Mitochondrial dynamics, oxidative stress, and apoptosis were evaluated through ATP measurement, western blotting and rotenone-mediated respiratory chain inhibition. Results: Our data indicated that pEVs outperformed cEVs in restoring renal function and histopathology. Additionally, a reduction in mitochondria-associated oxidative stress and cell death was observed. Proteomic profiling revealed that NO priming enriched pEVs with mitochondrial complex I components, which directly enhanced their bioenergetic capacity, as evidenced by higher mitochondrial complex I activity and elevated ATP production compared to cEVs. In vivo tracking confirmed targeted delivery of pEV-derived mitochondrial contents to renal tubular cells, reducing mitochondrial reactive oxygen species (ROS) and restoring mitochondrial mass. Crucially, mitochondria-depleted pEVs abolished these therapeutic effects, establishing mitochondrial cargos as the primary therapeutic driver. Furthermore, pEVs activated a pro-survival cascade in recipient cells, showing superior efficacy in promoting mitochondrial biogenesis, dynamics, and mitophagy, thereby restoring renal mitochondrial homeostasis. Conclusion: Our study elucidated a mitochondria-targeted therapeutic strategy enabled by engineered EVs that deliver functional cargo to restore mitochondrial homeostasis. These advances provide transformative potential for AKI and other mitochondrial disorders.

Keywords:  Acute kidney injury.; Extracellular vesicles; Mesenchymal stem cells; Mitochondrial homeostasis; Nitric oxide

DOI:  https://doi.org/10.7150/thno.113741
Eur J Pharmacol. 2025 Apr 24. pii: S0014-2999(25)00398-X. [Epub ahead of print] 177644

Antisense Oligonucleotides: A Promising Advancement in Neurodegenerative Disease Treatment.

Katarzyna Dudzisz, Ilona Wandzik.

  Antisense oligonucleotides (ASOs) are a class of therapeutics designed to modulate gene expression and have shown promise in the treatment of various neurodegenerative diseases. As of March 2025, four ASO-based therapies have received approval for the treatment of neurodegenerative diseases, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and hereditary transthyretin amyloidosis (ATTR). These approvals underscore the therapeutic potential of ASOs as effective treatments for neurodegenerative diseases by addressing specific genetic abnormalities. This is best demonstrated by clinical studies in more than a dozen ASOs, which could pave the way for the development of new therapeutics soon. Moreover, the ongoing extended clinical studies, which target presymptomatic carriers, have significant potential to cure familial ALS based on the SOD1 gene mutation. This review provides an update on clinical trials, highlighting promising results and the challenges encountered.

Keywords:  antisense oligonucleotides; clinical trials; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.ejphar.2025.177644
Cerebellum. 2025 Apr 29. 24(4): 90

Crossed Cerebellar Diaschisis in a Patient with MELAS Syndrome: A Case Report.

Ivana Karla Franić, Andreja Bujan Kovač, Branko Malojčić.

  Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare genetic disorder from a spectrum of mitochondrial diseases. Most commonly it presents with stroke-like symptoms, seizures, encephalopathy and myopathy. As it affects predominantly metabolically active organs, it can cause cardiomyopathy, diabetes mellitus, etc. We report a case of a young male patient with genetically proven MELAS who had a history of periodical generalized tonic-clonic seizures and then developed recurrent transient paresthesia of the right extremities, speech disturbance and apraxia. During work-up, an MRI done after a generalized tonic-clonic seizure showed hypoperfusion and edema in right cerebellar hemisphere caused by the contralateral cerebral acute ischemic lesion in left insular cortex which produced initial symptoms. This interesting finding is called crossed cerebellar diaschisis (CCD). CCD is a rare entity which refers to a decrease in metabolism, perfusion, and overall function in a cerebellar hemisphere because of a contralateral cerebral lesion. The disturbance of the function in an area distant from the location of initial brain lesion is possible because the two areas are connected via fiber tracts. This pathology most commonly occurs after ischemic stroke but also after seizures, supratentorial tumors, encephalitis etc. Our patient continued to have recurrent occasional transient paresthesia of the right extremities, but the follow-up MRI showed complete regression of hyperintensities in the left cerebral cortex and edema in right cerebellar hemisphere. In this paper we report co-existence of a rare neuroradiological finding such as CCD, in patient with rare cerebrovascular disease.

Keywords:  Cerebellar pathways; Crossed cerebellar diaschisis; Epilepsy; Ischemic lesion; MELAS

DOI:  https://doi.org/10.1007/s12311-025-01847-6
Neural Regen Res. 2025 Apr 29.

Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.

Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue.

   ABSTRACT: The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; calcium homeostasis; intervention strategy; mitochondria; mitochondrial dysfunction; mitochondrial membrane permeability transition pore; mitophagy; neurodegenerative diseases; oxidative stress; targeted therapy

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01507
BMJ. 2025 May 01. 389 r830

Patient passports have the potential to improve patient care.

Una MacFadyen.

DOI: https://doi.org/10.1136/bmj.r830
Arch Iran Med. 2025 Mar 01. 28(3): 140-148

Haplogroup Structure and Genetic Variation Analyses of Mitochondrial Genome SNPs in the Iranian Population.

Masoumeh Ghasemi, Marzieh Mohseni, Zohreh Fattahi, Masoud Edizadeh, Maryam Beheshtian, Fatemeh Keshavarzi, Khadijeh Jalalvand, Mohammadamin Omrani, Ali Khanbazi, Yasser Riazalhosseini, Mohammad Reza Akbari, Kimia Kahrizi, Hossein Najmabadi.

   BACKGROUND: Mitochondrial DNA (mtDNA) is a valuable marker for population studies and forensic investigations. Recent advancements in massively parallel sequencing technologies enable whole mitochondrial genome sequencing. This study collected blood samples from unrelated Iranian participants from four ethnic groups: Persian, Kurd, Lur, and Azeri. We mapped mtDNA haplogroups according to genetic ancestry and investigated the ethnic similarities within the Iranian population.
METHODS: Complete mtDNA sequences were generated with targeted mtDNA sequencing method and haplogroups were determined on the base of mitogenome polymorphisms. Additionally, we used data from the whole exome sequencing (WES) of the current samples to compare the variants identified by two different mitochondrial testing methods. Principal component analysis (PCA) calculations were performed using the R software to determine diversity between unrelated individuals of various ethnicities.
RESULTS: A total of 129 sub-haplogroups were identified in 15 main haplogroups. The findings revealed high frequencies of haplogroups U and H (22.4% and 20.3%, respectively) in the Iranian population. The PCA scatter plots revealed overlapping diversity, with no distinct trends separating the groups in these four groups within the Iranian population. In the present samples, the WES method identified only 57.8% of the variants detected by the targeted mtDNA sequencing method.
CONCLUSION: Variant studies do not show much difference, which indicate a small genetic difference between the central ethnic groups of Iran. Furthermore, comparing the targeted whole mitochondrial genome to mitochondrial data from WES in our study samples highlights the notion that targeted entire mitochondrial genome is a gold standard method for variant detection.

Keywords:  Genomic diversity; Haplogroup; Mitochondrial DNA; Targeted mtDNA sequencing method; Whole exome sequencing

DOI:  https://doi.org/10.34172/aim.33639