bims-curels 2025-04-20 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–04–20
nineteen papers selected by
Cure Mito Foundation

Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.
NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.
Leber Hereditary Optic Neuropathy With Magnetic Resonance Imaging Findings Suggestive of Optic Perineuritis and Optic Neuritis: A Diagnostic Challenge.
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
A population-based cohort study of mitochondrial disease and mental health conditions in Ontario, Canada.
Role of Comprehensive Renal Genetic Testing in Diagnosing a RMND-1 Mitochondrial Disease in Two Adult Cases Exhibiting Variable Disease Phenotypes.
Leber hereditary optic neuropathy with the homoplasmic m.14484 T > C mutation presenting initially with cerebellar ataxia.
Taurine supplementation improves physical activity level in a hemodialysis patient with mitochondrial disease: a case report.
Engineering mitochondrial DNA deletions in human cells improves disease modeling.
MtDNA 3243 A>G mutation and recurrent cholangitis after Kasai procedure in biliary atresia: a case report.
Use of alternative and confirmatory data in support of rare disease drug development.
An explainable dataset linking facial phenotypes and genes to rare genetic diseases.
Innovations and Best Practices for Therapeutic Development in Pediatric Rare Diseases: A Model-Informed Drug Development Perspective.
Widening Patient Engagement for Rare Disease Drug Trials: The Perspectives of Patients With Idiopathic Pulmonary Fibrosis on Participating in Clinical Drug Trials and Drug Trial Design.
Elevated circulating cell-free mitochondrial DNA level in cerebrospinal fluid of narcolepsy type 1.
Mitochondria in focus: From structure and function to their role in human diseases. A review.
The mitochondrial LONP1 protease: molecular targets and role in pathophysiology.
Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.
The limitations of narrative medicine.

Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102521

Optimization of mtDNA-targeted platinum TALENs for bi-directionally modifying heteroplasmy levels in patient-derived m.3243A>G-iPSCs.

Naoki Yahata, Yu-Ichi Goto, Ryuji Hata.

  Patient-derived induced pluripotent stem cells (iPSCs) are a useful pathological model for debilitating diseases caused by mitochondrial DNA (mtDNA) mutations. We established iPSCs derived from mitochondrial disease patients, heteroplasmic for the m.3243A>G mutation. The proportion of a selected mtDNA can be reduced by delivering a programmable nuclease into the mitochondria, and we developed various mtDNA-targeted Platinum TALENs (mpTALENs) to modify m.3243A>G-iPSC heteroplasmy levels in either wild-type or mutant direction. For TALEN optimization, the use of non-conventional repeat-variable di-residues (ncRVD)-LK/WK or NM-enhanced cleavage activity and specificity, and the replacement of conventional with obligate heterodimeric FokI nuclease domains increased target specificity and protected mtDNA from copy number depletion. In vitro, depending on whether wild-type or mutant mtDNA was targeted, we could obtain m.3243A>G-iPSCs with a higher or lower mutation load, while the cells retained their ability to differentiate into three germ layers. These results demonstrate that our mpTALEN optimization created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving the potential for studying mutation pathology. The enhanced efficiency also holds promise for using m.3243G(MUT)-mpTALEN as a therapeutic strategy for treating patients suffering from m.3243A>G mitochondrial diseases.

Keywords:  MELAS; MT: RNA/DNA Editing; diabetes mellitus; induced pluripotent stem cells, iPSCs; mitochondria; mitochondrial DNA, mtDNA; transcription activator-like effector nuclease, TALEN

DOI:  https://doi.org/10.1016/j.omtn.2025.102521
J Child Neurol. 2025 Apr 16. 8830738251328199

NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.

Bailyn Hogue, Mekka R Garcia, Connolly G Steigerwald, Maria J Borja, Nicolas J Abreu.

  Leigh syndrome is a progressive infantile neurodegenerative disorder of mitochondrial metabolism that often leads to decompensation in the setting of metabolic stress. It is genetically heterogenous with varied inheritance patterns. One subtype includes NDUFS8-related autosomal recessive Leigh syndrome. This nuclear gene encodes a complex I subunit of the mitochondrial complex chain. Although Leigh syndrome is typically associated with basal ganglia and brainstem involvement, cases of confluent white matter disease have been described with NDUFS8-related disorders. We present the case of a 6-month-old girl with initial imaging suggestive of a leukodystrophy, later found to have a novel homozygous variant in NDUFS8. In conjunction with the clinical course, a diagnosis of Leigh syndrome was made. This case highlights that mitochondrial disorders should be considered on the differential for confluent cerebral white matter disease in early childhood.

Keywords:  Leigh syndrome; NDUFS8; leukodystrophy; leukoencephalopathy; white matter

DOI:  https://doi.org/10.1177/08830738251328199
Cureus. 2025 Mar;17(3): e80439

Leber Hereditary Optic Neuropathy With Magnetic Resonance Imaging Findings Suggestive of Optic Perineuritis and Optic Neuritis: A Diagnostic Challenge.

Kazuhiro Horiuchi, Shuntaro Nakamura, Kazuki Yamada.

  Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder characterized by subacute, painless, and bilateral vision loss, typically affecting young men. LHON is caused by mitochondrial DNA mutations, most commonly m.11778G>A, m.14484T>C, and m.3460G>A. LHON has incomplete penetrance, with a higher prevalence in men, and its diagnosis is often delayed because of clinical overlap with other optic nerve disorders, such as optic neuritis. Herein, we report the case of a 37-year-old man presenting with progressive vision loss in both eyes over two months. Early magnetic resonance imaging (MRI) findings were suggestive of optic neuritis or peripapillary optic neuritis. Based on the MRI findings, the differential diagnoses for the patient's condition included multiple sclerosis, neuromyelitis optica spectrum disorders, anti-myelin oligodendrocyte glycoprotein (MOG) antibody-related diseases, sarcoidosis, Behçet's disease, systemic lupus erythematosus, Sjögren's syndrome, and idiopathic optic neuritis and peripapillary optic neuritis. The patient was treated with intravenous methylprednisolone and plasmapheresis. Despite immunotherapy, the patient's symptoms worsened. Comprehensive evaluation revealed normal cerebrospinal fluid and negative autoimmune markers. Mitochondrial DNA testing confirmed the m.11778G>A mutation, which led to the diagnosis of LHON. The patient was treated with ubidecarenone because of the unavailability of idebenone; however, no significant visual improvement occurred. His vision stabilized at 0.3 in the right eye, whereas the left eye became completely blind. This case highlights the diagnostic challenges of LHON, particularly when MRI findings mimic optic neuritis. The preservation of the pupillary light reflex and nonresponse to immunotherapy are key diagnostic clues. Early genetic testing is crucial in cases with atypical progression to confirm LHON and guide management. This case underscores the need for heightened awareness of the incidence of LHON in patients with subacute vision loss unresponsive to conventional treatments.

Keywords:  genetic testing; leber hereditary optic neuropathy; mitochondrial disease; optic neuritis; optic perineuritis

DOI:  https://doi.org/10.7759/cureus.80439
HGG Adv. 2025 Apr 15. pii: S2666-2477(25)00044-2. [Epub ahead of print] 100441

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts. Using dedicated pipelines to address the technical challenges posed by the mtDNA-circular genome, variant heteroplasmy, and nuclear misalignment-we called single nucleotide variants, small indels, and large mtDNA deletions from exome and/or genome sequencing data, in addition to RNA-sequencing data when available. Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one previously unreported likely pathogenic variant), as well as candidate diagnostic variants in a further 11 undiagnosed families. In one additional undiagnosed proband, detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair. Overall, mtDNA variant calling from data generated by exome and genome sequencing-primarily for nuclear variant analysis-resulted in a genetic diagnosis for 0.2% of undiagnosed families affected by a broad range of rare diseases, as well as identification of additional promising candidates.

DOI: https://doi.org/10.1016/j.xhgg.2025.100441
Orphanet J Rare Dis. 2025 Apr 14. 20(1): 177

A population-based cohort study of mitochondrial disease and mental health conditions in Ontario, Canada.

Laura C Rosella, Mackenzie Hurst, Emmalin Buajitti, Thomas Samson, L Trevor Young, Ana C Andreazza.

   BACKGROUND: Mitochondrial disease has been linked to mental health disorder in clinical cohorts and post-mortem studies. However, a lack of population-level studies examining the relationship between mitochondrial disease and mental health has resulted in an evidence gap and creates a challenge for identifying and addressing care needs for the mitochondrial disease population. Using multiple linked population health databases in a single-payer health system that covers the full population, this study aimed to investigate the prevalence of mood disorders and other mental health conditions in patients with mitochondrial disease and to examine the joint impact of mitochondrial disease and mental health conditions on healthcare use and health system costs. To contextualize these findings, a clinical comparator cohort of multiple sclerosis (MS) patients was analyzed.
RESULTS: Overall, co-prevalent mental health conditions are common in the mitochondrial population. Double the proportion of patients in the mitochondrial disease cohort had a co-prevalent mental health illness as compared to the MS population (18% vs 9%). Healthcare utilization was highest among patients with co-prevalent mitochondrial disease and mental illness, with 49% hospitalized within 1 year prior to cohort entry (compared to 12% of MS patients with no mental health condition). Costs were likewise highest among mitochondrial disease patients with mental health conditions.
CONCLUSIONS: This study presents the first comprehensive, population-wide cohort study of mitochondrial disease and co-prevalent mental health conditions. Our findings demonstrate a high burden of mental health conditions among mitochondrial disease patients, with high associated health care needs. We also find that patients with concurrent mental illness and mitochondrial disease represent a high-burden, high-cost population in a single-payer health insurance setting.

Keywords:  Epidemiology; Health care costs; Health care utilization; Mental health; Mitochondrial disease

DOI:  https://doi.org/10.1186/s13023-025-03688-2
Clin Case Rep. 2025 Apr;13(4): e70421

Role of Comprehensive Renal Genetic Testing in Diagnosing a RMND-1 Mitochondrial Disease in Two Adult Cases Exhibiting Variable Disease Phenotypes.

Quinn Stein, Ryan Mascarenhas, Sumit Punj, Maggie Westemeyer, Emily Hendricks, Tessa Pitman, Meg Hager, Nour Al Haj Baddar, Kristen Connors, Alexa Bacher, Robin Larson, Lauren Zec, Jennifer Stoddard.

  RMND1-related mitochondrial disease is a rare genetic condition that affects multiple organs, including the kidneys. We describe two adult patients whose diagnosis, initiated in childhood, was established through renal gene panel testing, emphasizing the value of genetic testing in uncovering kidney-related conditions that have a high degree of clinical heterogeneity.

Keywords:  RMND1; RMND1‐related mitochondrial disease; genetic testing; kidney gene panel

DOI:  https://doi.org/10.1002/ccr3.70421
J Neurol. 2025 Apr 18. 272(5): 347

Leber hereditary optic neuropathy with the homoplasmic m.14484 T > C mutation presenting initially with cerebellar ataxia.

Zhandong Qiu, Yan Han, Xixi Yang, Mengyao Zhang, Dawei Li, Zheng Liu.

DOI: https://doi.org/10.1007/s00415-025-13014-2
CEN Case Rep. 2025 Apr 16.

Taurine supplementation improves physical activity level in a hemodialysis patient with mitochondrial disease: a case report.

Ryuto Yoshida, Ryunosuke Mitsuno, Takashin Nakayama, Tatsuhiko Azegami, Akinori Hashiguchi, Takuto Torimitsu, Norifumi Yoshimoto, Akihito Hisikawa, Aika Hagiwara, Toshifumi Nakamura, Shu Meguro, Masahiro Katsumata, Jin Endo, Tatsuo Matsunaga, Jun Yoshino, Takeshi Kanda, Kohkichi Morimoto, Toshiaki Monkawa, Tadashi Yoshida, Jin Nakahara, Shintaro Yamaguchi, Kaori Hayashi.

  Mitochondrial diseases (MDs) are inherited metabolic disorders that affect multiple organ systems, including the kidneys. Variability in disease onset and phenotypic expression, combined with the absence of specific kidney pathological findings, pose significant challenges in diagnosing MD. Consequently, many undiagnosed cases of MD may exist among patients undergoing dialysis. No effective treatment for mitochondrial nephropathy has been established. We report the case of a 27-year-old female patient who presented with leg edema, nephrotic range proteinuria attributed to focal segmental glomerulosclerosis, and bilateral sensorineural hearing loss. Immunosuppressive therapy failed to achieve remission, resulting in progressive kidney function decline and eventual end-stage kidney disease. At hemodialysis initiation, worsening atypical cardiac function and hypertrophy prompted genetic testing, which identified an MT-TL1 m.3243 A > G mutation and confirmed the diagnosis of MD. After hemodialysis initiation, the patient experienced persistent fatigue and decreased physical activity levels despite dry weight management. Suspected stroke-like symptoms prompted the initiation of taurine supplementation, which significantly improved headache severity, cardiac function, and physical activity levels. This case highlights the therapeutic potential of taurine supplementation in patients with MD undergoing dialysis and the importance of maintaining clinical vigilance for MD across all stages of chronic kidney disease, even without characteristic renal pathological findings of mitochondrial nephropathy.

Keywords:  Focal segmental glomerulosclerosis; Mitochondrial disease; Taurine

DOI:  https://doi.org/10.1007/s13730-025-00992-5
Nat Biotechnol. 2025 Apr;43(4): 501

Engineering mitochondrial DNA deletions in human cells improves disease modeling.

Iris Marchal.

DOI: https://doi.org/10.1038/s41587-025-02652-6
Transl Pediatr. 2025 Mar 31. 14(3): 522-528

MtDNA 3243 A>G mutation and recurrent cholangitis after Kasai procedure in biliary atresia: a case report.

Jie Sun, Yanan Zhang, Dayan Sun, Jinshi Huang.

   Background: Cholangitis following the Kasai procedure contributes to a poor prognosis in biliary atresia (BA). We report a case of a pediatric patient with BA who developed recurrent cholangitis after undergoing a Kasai procedure and was subsequently found to carry the mitochondrial DNA (mtDNA) 3243 A>G mutation.
Case Description: This case involves a 7-month-old female infant who, at 2 months of age, exhibited symptoms including jaundice, stool discoloration, and dark urine, prompting a diagnosis of hyperbilirubinemia. Hepatobiliary dynamic imaging suggested BA, a diagnosis confirmed by abdominal ultrasound and laparoscopic exploration at our hospital. She underwent a Kasai procedure and was discharged on day 19. However, recurrent, treatment-resistant cholangitis subsequently led to her readmission. Given the patient's complex clinical course, genetic testing, conducted with informed consent, revealed a pathogenic mtDNA variant at position 3243 (A>G). Due to the severity of her condition, she underwent liver transplantation 5 months after the Kasai procedure.
Conclusions: This article reports a rare case of the mtDNA 3243 A>G mutation presenting as recurrent cholangitis, suggesting that mitochondrial dysfunction may consistently induce inflammation. This case highlights the importance of recognizing mitochondrial mutations in BA due to their critical impact on the patient's prognosis. A comprehensive genetic evaluation may benefit patients with BA accompanied by recurrent cholangitis.

Keywords:  Biliary atresia (BA); case report; cholangitis; genetic analysis; mitochondrial DNA mutation (mtDNA mutation)

DOI:  https://doi.org/10.21037/tp-2024-592
J Biopharm Stat. 2025 Apr 11. 1-15

Use of alternative and confirmatory data in support of rare disease drug development.

Shein-Chung Chow, Anne Pariser, Steven Galson.

  Recently, the use of alternative and confirmatory data in support of rare disease drug development has received much attention (NASEM 2024). This article attempts to provide an overview regarding the limitations and major challenges of the use of ACD that are commonly encountered in rare disease drug (including biologics) product development. In addition, some innovative approaches using ACD under a novel two-stage hybrid adaptive trial design are proposed to assist the sponsors in rare disease drug development are proposed. Under the proposed hybrid adaptive trial design, statistical considerations regarding the implementation of ACD in support of the demonstration of the safety and efficacy in rare disease drug development are discussed.

Keywords:  Real-world data and real-world evidence (RWD/RWE); Substantial evidence; alternative and confirmatory evidence (ACE); hybrid adaptive trial design

DOI:  https://doi.org/10.1080/10543406.2025.2489279
Sci Data. 2025 Apr 15. 12(1): 634

An explainable dataset linking facial phenotypes and genes to rare genetic diseases.

Jie Song, Mengqiao He, Shumin Ren, Bairong Shen.

Distinctive facial phenotypes serve as crucial diagnostic markers for many rare genetic diseases. Although AI-driven image recognition achieves high diagnostic accuracy, it often fails to explain its predictions. In this study, we present the Facial phenotype-Gene-Disease Dataset (FGDD), an explainable dataset collected from 509 research publications. It contains 1,147 data records encompassing 197 disease-causing genes, 437 facial phenotypes, and 211 disease entities, with 689 records having disease labels. Each data record represents a patient group and includes demographic information, variation information, and phenotype information. Baseline and explainability validations conducted on FGDD confirmed the dataset's effectiveness. FGDD supports the training of diagnostic models for rare genetic diseases while delivering explainable results, and provides a foundation for exploring intricate connections between genes, diseases, and facial phenotypes.

DOI: https://doi.org/10.1038/s41597-025-04922-z
Clin Pharmacol Ther. 2025 Apr 16.

Innovations and Best Practices for Therapeutic Development in Pediatric Rare Diseases: A Model-Informed Drug Development Perspective.

Rajesh Krishna, Satyendra Suryawanshi, Juliane Rascher, Sonja Hartmann, Bernard Sebastien, Jeffrey S Barrett.

Emerging innovations in pediatric rare diseases are offering up the opportunity to fundamentally change the way therapeutic development in pediatric rare diseases is enabled, largely through the application of model-informed drug development (MIDD). Pediatric rare diseases, often characterized by small patient populations, patient heterogeneity that is compounded by differences in adult and pediatric diseases, and limited development options, pose significant challenges in drug development. The ICH E11(R1) addendum particularly calls out the value of modeling and simulation and other statistical approaches in extrapolation and filling the gaps in knowledge and/or reducing uncertainties. Therefore, MIDD provides a powerful solution by enabling more efficient, data-driven decision-making, reducing the need for large, costly trials while ensuring that clinical endpoints are both relevant and feasible. MIDD approaches have been able to extrapolate the treatment responses from adults to pediatrics, making decisions around the viability of targets and dose selection simpler. In this whitepaper, we build on our previous results by critically examining the role of biomarkers and surrogate endpoints, statistical innovations, and modeling and simulation best practices as they apply to pediatric rare diseases therapeutic development. We posit that the effective integration of digital biomarkers, patient-reported outcomes, and quality of life methodologies into the development of therapies for pediatric rare diseases will catalyze a significant shift towards more personalized, patient-centered approaches in this vulnerable population.

DOI: https://doi.org/10.1002/cpt.3683
Health Expect. 2025 Apr;28(2): e70260

Widening Patient Engagement for Rare Disease Drug Trials: The Perspectives of Patients With Idiopathic Pulmonary Fibrosis on Participating in Clinical Drug Trials and Drug Trial Design.

Widening Engagement Patient Advisory Group

   BACKGROUND: Research about patient engagement for people with rare diseases has identified how the experiences of some members of the public are overlooked in relation to clinical trial design and trial participation. As part of a knowledge transfer partnership (KTP), the authors were granted access to patient insight reports about the needs of people with idiopathic pulmonary fibrosis (IPF), to inform clinical trial design and marketing strategy. These were contrasted with data from qualitative interviews, informed by and collected from people with IPF and the clinical staff who recruit them to trials.
OBJECTIVE: To identify patient and professional perspectives for IPF drug trials to create opportunities for innovation in patient engagement.
DESIGN: Ethnography. Qualitative researcher embedded in a pharmaceutical organisation.
SETTING AND PARTICIPANTS: International patient insight reports to inform a clinical trial protocol (n = 1) and marketing strategy (n = 6), including the experiences of over 100 patients with IPF. In the United Kingdom, interviews with patients with IPF (n = 32) and the staff who support them clinically and recruit them to trials of new medicines (n = 19) at one specialist interstitial lung disease (ILD) centre.
RESULTS: Methodological practices inherent in inpatient insight reports ensured the perspectives of some people with IPF were overlooked. Interviews with a more marginalised population of people with IPF, and the staff who support them, identified that some found trial information confusing, trial practices frustrating and the opportunities to engage in trial design absent.
DISCUSSION: Current pharmaceutical practices of working with contract research organisations and patient organisations exclude the perspectives of patients with IPF who do not engage with either. Trial recruitment information needs to be tailored to the needs of individuals, and trial processes need to enable a wider group of patients to participate.
CONCLUSIONS: People with IPF want the opportunity to participate in drug trials and trial science. However, methodological rigour and deliberative practices are required to enable a wider group of patients to have a stake in the design and conduct of drug trials for rare diseases. The challenge now is for regulators to mandate such inclusive practices and for pharmaceutical organisations to adopt them.
PATIENT OR PUBLIC CONTRIBUTION: A Patient Advisory Group (PAG) comprising six people with IPF gave input on the research protocol and then on the scope and content of the ongoing research. Two patients from international patient organisations served as a Steering Group (SG). Members of these groups provided their interpretations of the study findings and gave insight on their experiences in clinical design and participation.

Keywords:  idiopathic pulmonary fibrosis; market access; patient engagement; qualitative research; randomised controlled trials; rare diseases

DOI:  https://doi.org/10.1111/hex.70260
Brain Commun. 2025 ;7(2): fcaf125

Elevated circulating cell-free mitochondrial DNA level in cerebrospinal fluid of narcolepsy type 1.

Monica Moresco, Concetta Valentina Tropeano, Martina Romagnoli, Giulia Neccia, Alessandro Rapone, Fabio Pizza, Stefano Vandi, Emmanuel Mignot, Alessandra Maresca, Valerio Carelli, Giuseppe Plazzi.

  Narcolepsy type 1 (NT1) is a rare neurological disorder characterized by excessive daytime sleepiness and cataplexy, thought to result from an autoimmune process targeting the hypothalamic hypocretin-producing neurons. Aiming to add clues to the latter hypothesis, we investigated circulating cell-free mitochondrial DNA (ccf-mtDNA) levels in cerebrospinal fluid (CSF), a possible biomarker for neurodegeneration, neuroinflammation or immune activation, from 46 NT1 patients with low CSF hypocretin-1, compared with 32 controls. We found significantly increased ccf-mtDNA levels in NT1 patients compared with controls, which negatively correlated with CSF hypocretin-1 concentrations. Additionally, higher ccf-mtDNA levels were observed in patients with elevated number of sleep onset rapid eye movement periods. These observations imply that increased levels of ccf-mtDNA associate with reduced CSF hypocretin-1 concentrations leading to greater alteration in sleep architecture. Furthermore, cytokine profiling in CSF revealed significant changes in interleukins 6 and 18 in NT1 patients, suggesting an active neuroinflammatory process possibly linked to ccf-mtDNA release, thus pointing to a specific inflammatory signature in NT1. These findings hint a potential mitochondrial dysfunction and neuroinflammation in NT1. Further studies are needed to elucidate the underlying mechanisms and how this may reflect on therapy.

Keywords:  cerebrospinal fluid; circulating cell-free mitochondrial DNA; cytokines; hypocretin 1; narcolepsy type 1

DOI:  https://doi.org/10.1093/braincomms/fcaf125
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2025 Apr 14.

Mitochondria in focus: From structure and function to their role in human diseases. A review.

Daniel Follprecht, Jakub Vavricka, Viktorie Johankova, Pavel Broz, Ales Krouzecky.

  Mitochondria, double-membraned organelles within all eukaryotic cells, are essential for the proper functioning of the human organism. The frequently used phrase "powerhouses of the cell" fails to adequately capture their multifaceted roles. In addition to producing energy in the form of adenosine triphosphate through oxidative phosphorylation, mitochondria are also involved in apoptosis (programmed cell death), calcium regulation, and signaling through reactive oxygen species. Recent research suggests that they can communicate with one another and influence cellular processes. Impaired mitochondrial function on the one hand, can have widespread and profound effects on cellular and organismal health, contributing to various diseases and age-related conditions. Regular exercise on the other hand, promotes mitochondrial health by enhancing their volume, density, and functionality. Although research has made significant progress in the last few decades, mainly through the use of modern technologies, there is still a need to intensify research efforts in this field. Exploring new approaches to enhance mitochondrial health could potentially impact longevity. In this review, we focus on mitochondrial research and discoveries, examine the structure and diverse roles of mitochondria in the human body, explore their influence on energy metabolism and cellular signaling and emphasize their importance in maintaining overall health.

Keywords:  mitochondria; mitochondrial disease; mitochondrial function; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.5507/bp.2025.009
Mol Biol Rep. 2025 Apr 18. 52(1): 401

The mitochondrial LONP1 protease: molecular targets and role in pathophysiology.

Pei Tang, Qun Zeng, Yihao Li, Jing Wang, Meihua She.

  Lon peptidase 1 (LONP1), a member of the AAA + family, is essential for maintaining mitochondrial function. Recent studies have revealed that LONP1 serves as a multifunctional enzyme, acting not only as a protease but also as a molecular chaperone, interacting with mitochondrial DNA (mtDNA), and playing roles in mitochondrial dynamics, oxidative stress, cellular respiration, and energy metabolism. LONP1 is evolutionarily highly conserved, and mutations or dysfunctions in LONP1 can lead to diseases. There is growing evidence linking LONP1 to various human diseases, such as tumors, neurodegenerative diseases, and heart diseases. This review discusses the discovery, molecular structure, subcellular localization, tissue distribution, and mitochondrial function of LONP1. Furthermore, it summarizes the associations between LONP1 and tumors, neurodegenerative diseases, and heart diseases, exploring its role in different diseases and potential molecular mechanisms. It also analyzes the regulatory effects of related inhibitors and agonists on LONP1. Considering the pleiotropic effects of LONP1, the study of LONP1 is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.

Keywords:  Heart disease; LONP1; Mitochondria; Neurodegenerative disease; Tumor

DOI:  https://doi.org/10.1007/s11033-025-10500-8
BMC Neurol. 2025 Apr 16. 25(1): 160

Investigating the genetic association of mitochondrial DNA copy number with neurodegenerative diseases.

Huan Xia, Zi-Hao Wang, Xiao-Bei Wang, Mei-Rong Gao, Sen Jiang, Xin-Yu Du, Xin-Ling Yang.

   OBJECTIVE: This study aims to investigate the causal relationship between Mitochondrial DNA (mtDNA) copy number and several common neurodegenerative diseases (NDs).
METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS) as instrumental variables (IVs). After screening for relevance and potential confounders, we estimated the association between mtDNA copy number and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS). Additionally, we validated our findings using GWAS data on mtDNA copy number from Longchamps et al., sourced from the Genetics Epidemiology Consortium and the UK Biobank (UKB) aging study cohort.
RESULTS: A GWAS analysis of 395,718 UKB participants found no significant association between mtDNA copy number and the risk of NDs, including AD (OR = 0.956, P = 0.708), PD (OR = 1.223, P = 0.179), ALS (OR = 0.972, P = 0.374), and MS (OR = 0.932, P = 0.789). Similarly, reverse MR analysis revealed no significant relationship between genetic predictions of NDs and mtDNA copy number: AD (OR = 0.987, P = 0.062), PD (OR = 0.997, P = 0.514), ALS (OR = 0.974, P = 0.706), and MS (OR = 1.003, P = 0.181).
CONCLUSION: Although mitochondrial dysfunction is implicated in the pathogenesis of NDs, no clear evidence supports a causal role for mtDNA copy number. The relationship between mtDNA copy number and NDs is likely mediated by more complex molecular regulatory mechanisms. Further research is required to elucidate these intricate interactions.

Keywords:  Genome-wide association studies; Mendelian randomization analysis; Mitochondrial DNA copy number; Neurodegenerative diseases

DOI:  https://doi.org/10.1186/s12883-025-04176-7
Theor Med Bioeth. 2025 Apr 16.

The limitations of narrative medicine.

Rajeev Dutta.

  Narrative medicine has emerged over the past few decades as an exciting approach to medical practice, interweaving the practice of medicine with the practices of literary analysis and reflective writing. It is often claimed that narrative medicine enables practitioners to understand and empathize with patient stories, effectively 'joining' patients in illness. However, I argue that there are reasons to be suspicious of narrative medicine's ability to promote patient-centered care. I begin by questioning the distinctiveness of narrative knowledge, suggesting that it is neither able to be propositional knowledge ('knowledge-that') nor phenomenal/experiential knowledge ('knowledge-what-it's-like'). Then, I consider an alternative reading of narrative medicine, by which narratives are simply ways to structure patient information so that a physician can more readily empathize with the patient. I dismiss this alternative as unsatisfactory given that it depends on either all patients building narratives or physicians imposing narrative structure(s) where one does not inherently exist, thus overriding patients. Finally, I provide possible supplements and alternatives to narrative medicine, proposing that active listening and the removal of systemic barriers to physicians' abilities to provide humanistic care (e.g., lower administrative, profit, and documentation burdens) may be a first step to putting empathetic patient care on the forefront. Ultimately, I think that these efforts (while their fruition may present difficulty), rather than sifting through patient information to construct and elevate narratives, present the opportunity to accurately refocus patient-centered care.

Keywords:  Active listening; Empathy; Epistemology; Narrative knowledge; Narrative medicine

DOI:  https://doi.org/10.1007/s11017-025-09713-6