bims-curels 2025-08-10 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–08–10
ten papers selected by
Cure Mito Foundation

Mitochondrial disease management through phytochemical interventions.
Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.
Transforming Pediatric Rare Disease Drug Development: Enhancing Clinical Trials and Regulatory Evidence With Virtual Patients.
Reframing primary mitochondrial disease as a sterile interferonopathy.
Engaging Essential Patient Support Personnel in Research as Patient Partners: A Survey Study.
Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.
Clinical features, disease burden and impact on quality of life in participants with mitochondrial encephalomyopathy.
Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.
Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.
Updates on Mitochondrial Myopathies.

Mol Cell Biochem. 2025 Aug 03.

Mitochondrial disease management through phytochemical interventions.

R Prabhu Ramya, K B Megha, S Reshma, M J Ajai Krishnan, S Amir, Rashmi Sharma, P V Mohanan.

  Mitochondrial diseases are a diverse group of disorders caused by dysfunction in mitochondria, the energy-generating organelles of cells. These disorders result from mutations in either nuclear or mitochondrial DNA and can be classified as primary (genetic origin) or secondary (environmentally induced). Due to their systemic impact, mitochondrial dysfunction leads to a wide range of clinical symptoms varying from tissue type and patient age. This review aims to provide a comprehensive overview of mitochondrial diseases, focusing on their classification, pathophysiology, diagnostic challenges and emerging therapeutic strategies. Current diagnostic approaches face limitations due to the complexity and heterogeneity of mitochondrial disorders. Recent evidence highlights the potential of phytochemicals such as polyphenols, flavonoids, alkaloids and terpenoids in modulating mitochondrial function. These natural compounds can enhance mitochondrial biogenesis, reduce oxidative stress and improve cellular energy metabolism. Phytochemicals represent a promising therapeutic avenue for mitigating mitochondrial dysfunction. However, further research is needed to validate their efficacy and develop standardized treatment protocols. An improved understanding of the molecular mechanisms involved in mitochondrial pathology will aid in developing more targeted diagnostic and therapeutic strategies.

Keywords:  Mitochondrial biogenesis; Mitochondrial diseases; Oxidative stress; Phytochemicals; Therapeutic strategies

DOI:  https://doi.org/10.1007/s11010-025-05360-6
Pediatr Radiol. 2025 Aug 07.

Retrospective observational study of the magnetic resonance imaging features of MPV17-related mitochondrial DNA depletion syndrome.

Suzanne O'Hagan, Surita Meldau, Penelope Rose, Magriet Van Niekerk, Christelle Ackermann, Gillian Riordan, Ronald Van Toorn.

   BACKGROUND: MPV17-related mitochondrial deoxyribonucleic acid (DNA) maintenance defects present in most affected individuals as an early-onset encephalohepatopathic disease. Diagnosis requires comprehensive molecular genetic testing, which is often not available in resource-limited settings. Therefore, the role of imaging as a diagnostic tool necessitates further exploration. Herein, we present the largest known cohort of patients with genetically confirmed MPV17-related mitochondrial DNA depletion syndrome, highlighting in detail the neuroimaging findings.
OBJECTIVE: To establish novel features on magnetic resonance imaging (MRI) that characterise MPV17-related mitochondrial DNA depletion syndrome, in order to provide a non-invasive, accessible, and reproducible biomarker inquiry.
MATERIALS AND METHODS: Retrospective, descriptive study based at a large tertiary level hospital. Eight patients with MPV17-related mitochondrial DNA depletion syndrome who had undergone brain MRI were identified between 2015 and 2023. Neuroimaging findings were captured and described in detail. Two board-certified radiologists with experience in paediatric neuroradiology reviewed all images by consensus.
RESULTS: All patients were homozygous for the MPV17: c.106C>T variant. Age at brain MRI ranged from 11 days to 8 months. Seven out of the eight patients showed signal abnormalities in the reticulospinal tracts and/or reticular formation. Other neuroimaging findings included leukoencephalopathy, injury to extra-reticular white matter tracts and frequent basal ganglia involvement. Newly identified areas of involvement include the perirolandic cortices, hippocampi, optic pathways and olfactory nerves.
CONCLUSION: Lesions in the reticular formation and reticulospinal tracts on brain MRI in a neonate or infant with hepatic dysfunction may represent a distinctive, albeit not specific, feature of MPV17-related mitochondrial DNA depletion syndrome.

Keywords:  MPV17 mitochondrial DNA depletion syndrome; Mitochondrial DNA; Mitochondrial disease; Neuroimaging; Pediatric; Resource-limited settings; Reticular formation

DOI:  https://doi.org/10.1007/s00247-025-06341-z
CPT Pharmacometrics Syst Pharmacol. 2025 Aug 04.

Transforming Pediatric Rare Disease Drug Development: Enhancing Clinical Trials and Regulatory Evidence With Virtual Patients.

Fianne Sips, Marco Virgolin, Giuseppe Pasculli, Federico Reali, Alessio Paris, Annette Janus, Yann Godfrin, Daniel Röshammar, Luca Marchetti, Jane Knöchel.

Drug development in pediatric rare diseases is complicated by practical and ethical constraints on clinical trial design, stemming from small, highly heterogeneous, and vulnerable patient populations. Virtual patients (VPs) created with machine-learning (ML), mechanistically driven computational approaches, or hybrids thereof, have the potential to expedite and maximize the impact of trials. We discuss the potential of VPs to transform the efficiency and impact of clinical trials in pediatric rare diseases, based on adult and pediatric examples.

DOI: https://doi.org/10.1002/psp4.70096
Mol Genet Metab. 2025 Jul 30. pii: S1096-7192(25)00208-2. [Epub ahead of print]146(1-2): 109217

Reframing primary mitochondrial disease as a sterile interferonopathy.

Eva Morava, Ibrahim Elsharkawi, Tamas Kozicz.

DOI: https://doi.org/10.1016/j.ymgme.2025.109217
Risk Manag Healthc Policy. 2025 ;18 2529-2537

Engaging Essential Patient Support Personnel in Research as Patient Partners: A Survey Study.

Christine Skubisz, Shayna DeRosa, Carly R Pacanowski.

   Introduction: Patient engagement in research is a collaborative interaction between patients and researchers throughout the entire research process. Healthcare workers provide care for others, but are the patients themselves in areas of workplace safety and mental health. Essential patient support personnel working on the front line of healthcare are particularly vulnerable but have an underrepresented voice in the research conducted about their health and work.
Methods: To explore this topic, a survey study of essential patient support personnel (N=42), guided by the Integrated Model of Behavioral Prediction, measured attitudes about engagement, behavioral intentions, and past engagement behavior. Skills and constraints, predictors of behavioral intentions for engagement in the model, were also assessed.
Results: Results showed that essential patient support personnel had positive attitudes and positive behavioral intentions to engage in research, yet only two participants had engaged in research in the past. Participants reported the most positive behavioral intentions to contribute at the preparation stage of research. Overwhelmingly, participants reported that the most important skill essential patient support personnel bring to a research team is their first-hand experience. Significant constraints to engagement included a lack of time, insufficient compensation, and job burnout.
Conclusion: Efforts to bolster patient engagement in research should focus on increasing the skills necessary for study execution (eg, study design and data analysis) and removing constraints to contribution (eg, providing appropriate monetary compensation, being mindful of time and heavy work schedules).

Keywords:  healthcare workers; integrated model of behavioral prediction; patient centered outcomes research; patient engagement in research; survey research

DOI:  https://doi.org/10.2147/RMHP.S512398
Stem Cells Transl Med. 2025 Jul 24. pii: szaf032. [Epub ahead of print]14(8):

Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.

Ashok R Dinasarapu, Diane J Sutcliffe, Lauren Grychowski, Erkin Ozel, Anika Thite, Jasper E Visser, Ellen J Hess, Sharon M Kolk, H A Jinnah.

  Induced pluripotent stem cells (iPSCs) are widely used to model human genetic diseases. The most common strategy involves collecting cells from relevant individuals and then reprogramming them into iPSCs. This strategy is very powerful, but finding enough individuals with a specific genetic disease can be challenging, especially since most are rare. In addition, making numerous iPSC lines is time-consuming and expensive. As a result, most studies have included relatively small numbers of iPSC lines, sometimes from the same individual. Considering the experimental variability obtained using different iPSC lines, there has been great interest in delineating the most efficient number of lines needed to achieve a robust and reproducible result. Several recommendations have been published, although most conclusions have been based on methods where experimental variance from individual cases is difficult to separate from technical issues related to the preparation of iPSCs. The current study used gene expression profiles determined by RNA sequencing (RNAseq) to empirically evaluate the impact of the number of unique individuals and the number of replicate iPSC lines from each individual for modeling Lesch-Nyhan disease (LND). This disease is caused by mutations in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase. Results for detecting disease-relevant changes in gene expression depended on the analytical method employed, and whether or not statistical procedures were used to address multiple iPSC lines from the same individual. In keeping with prior studies, the best results were obtained with iPSC lines from 3-4 unique individuals per group. In contrast to prior studies, results were improved with 2 lines per individual, without statistical corrections for duplicate lines from the same individual. In the current study where all lines were produced in parallel using the same methods, most variance in gene expression came from technical factors unrelated to the individual from whom the iPSC lines were prepared.

Keywords:   HPRT1 ; Lesch–Nyhan disease; disease modeling; human; induced pluripotent stem cell; transcriptome

DOI:  https://doi.org/10.1093/stcltm/szaf032
Front Neurol. 2025 ;16 1585906

Clinical features, disease burden and impact on quality of life in participants with mitochondrial encephalomyopathy.

John Sieh Dumbuya, Chuan Tian, Lin Deng, Bashir Ahmad, Xiuling Chen, Jun Lu.

   Background: Mitochondrial encephalomyopathy (ME) is a rare genetic disorder that significantly impacts participants' quality of life and places emotional and financial burdens on caregivers. However, the dynamics between perceived financial burden, disability, and caregiver strain are not fully understood. This study aimed to explore the differences in perceived financial burden, QoL, disability levels, and caregiver burden among participants with ME.
Methods: Between January and December 2023, we conducted a cross-sectional analysis of ME participants and their caregivers at Haikou Affiliated Hospital of Xiangya Medical College, Central South University. Multiple assessment scales, including CHU-9D, PedsQL, PHQ-9, and CBI, were used to evaluate disease burden, QoL, disability, and caregiver burden. Descriptive statistics and correlation coefficients were employed to assess the relationships between these factors.
Results: A total of 27 participants with ME were identified, with a mean age of 10.14 years, 88.9% of whom were children. The cohort comprised 18 (66.7%) males and 9 (33.3%) females; MELAS and Leigh syndrome were the most common subtypes. Significant correlations were found between QoL scores and caregiver burden, with CHU-9D showing negative correlations with PHQ-9 and CBI and positive correlations with PedsQL and health utility scores. Additionally, 44.4% of participants reported severe financial burdens, and 57.7% of caregivers experienced moderate to severe levels of burden.
Conclusion: Our findings highlight the complex relationships between financial strain, QoL, and caregiver burden in ME. This underscores the need for comprehensive, patient-centered care and targeted policy interventions to alleviate patient and caregiver burdens. Further research is essential to develop effective support systems and improve overall outcomes.

Keywords:  assessment scales; caregiver burden; financial burden; mitochondrial encephalomyopathy; quality of life; rare diseases

DOI:  https://doi.org/10.3389/fneur.2025.1585906
Cell Prolif. 2025 Aug 06. e70109

Pioglitazone Ameliorates Mitochondrial Oxidative Stress and Inflammation via AMPK-Dependent Inhibition of Mitochondrial Fission in Leigh Syndrome.

Jie Luo, Ling Chen, Xiaoxian Zhang, Qiang Su, Xiaoya Zhou, Qizhou Lian.

Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).

DOI: https://doi.org/10.1111/cpr.70109
Muscles. 2024 Nov 26. 3(4): 393-403

Noninvasive Assessments of Mitochondrial Capacity in People with Mitochondrial Myopathies.

Kevin K McCully, Hannah M Bossie, Fran D Kendall.

  People affected by mitochondrial myopathies (MITOs) are thought to have impaired skeletal muscle oxygenation. The aims of this study were to measure skeletal muscle mitochondrial capacity in MITO participants and able-bodied (AB) participants and evaluate the influence of muscle-specific endurance training in one MITO participant. Participants (n = 7) with mitochondrial disease and controls (n = 9) were tested (ages 18-54 years). Mitochondrial capacity (mVO2max) was measured using the rate constant of recovery of oxygen consumption (mVO2) after exercise in the forearm flexor muscles with near-infrared spectroscopy (NIRS). One MITO participant was tested before and after performing 18 forearm exercise sessions in 30 days. There were no differences between MITO and AB participants in mVO2max (MITO: 1.4 ± 0.1 min-1; AB: 1.5 ± 0.3 min-1; p = 0.29), resting mVO2 (MITO: -0.4 ± 0.2%/min; AB: -0.3 ± 0.1%/min; p = 0.23), or initial post exercise oxygen consumption rates (MITO: 4.3 ± 1.2%/min; AB: 4.4 ± 1.4%/min; p = 0.9). Exercise oxygen desaturation was greater in MITO (39.8 ± 9.7% range) than in AB (28 ± 8.8% range) participants, p = 0.02. The MITO participant who trained increased her mitochondrial capacity (58%) and muscle-specific endurance (24%) and had reduced symptoms of muscle fatigue. We found no evidence supporting in vivo impairment of forearm muscle mVO2max in genetically confirmed MITO participants. This is consistent with studies that report increased mitochondrial content, which offsets the decrease in mitochondrial function. Positive muscle adaptations to endurance training appear to be possible in people with MITOs. Characterization of study populations will be important when interpreting the relationship between in vivo mitochondrial capacity and mitochondrial disease.

Keywords:  Kearns–Sayre syndrome; MELAS; NIRS; near-infrared spectroscopy; skeletal muscle

DOI:  https://doi.org/10.3390/muscles3040033
Curr Neurol Neurosci Rep. 2025 Aug 04. 25(1): 55

Updates on Mitochondrial Myopathies.

Emanuele Barca, Valentina Emmanuele.

   PURPOSE OF REVIEW: Mitochondrial myopathies (MM) are a genetically and clinically heterogeneous group of disorders that remain underrecognized in adult and pediatric neurology. This review aims to provide a clinically useful tool for guiding diagnosis and management of MM. We also highlight the rapidly evolving diagnostic and therapeutic landscape, including novel diagnostic approaches and disease-modifying interventions.
RECENT FINDINGS: Large cohort data highlight key clinical subtypes - fixed myopathies, syndromic forms, and metabolic myopathies- with distinct diagnostic implications. Novel tools such as GDF-15, long-read mtDNA sequencing, and multi-omic approaches are enhancing diagnostic sensitivity. Emerging therapies for TK2 deficiency and precision mitochondrial gene editing are progressing rapidly, with several nearing regulatory decisions. Numerous preclinical therapeutic strategies are currently under development, offering promise for improving outcomes in these otherwise devastating disorders. Recognizing MM in clinical settings is essential for timely diagnosis, to guide prognosis and family planning as well as provide access to emerging treatment. A tiered diagnostic approach and integration of new genomic technologies can improve outcomes.
HUMAN AND ANIMAL RIGHTS: This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords:  Exercise intolerance; Mitochondrial myopathy; Muscle biopsy; Next-generation sequencing; Rhabdomyolysis; TK2 deficiency

DOI:  https://doi.org/10.1007/s11910-025-01444-4