bims-curels 2025-02-02 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2025–02–02
ten papers selected by
Cure Mito Foundation

NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.
Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.
Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.
Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.
Rare Disease Policy in High-Income Countries: An Overview of Achievements, Challenges, and Solutions.
Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases: mechanisms, prospective, and challenges.
Mitochondrial base editing: from principle, optimization to application.
Ethical Challenges in Pediatric Medical Complexity: A Survey of Parents.
The impact of a patient advisory board on a clinical comparative effectiveness trial: a comparison of patient and researcher perspectives.

Biomolecules. 2024 Dec 31. pii: 38. [Epub ahead of print]15(1):

NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.

Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Chika Watanabe, Eriko F Jimbo, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Kei Murayama, Akira Ohtake, Ryozo Nagai, Hitoshi Osaka, Kenichi Aizawa.

  Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD+. Utilizing this technique, we quantified NADH and NAD+ levels in fibroblasts derived from pediatric patients and in a Leigh syndrome mouse model in which mitochondrial respiratory chain complex I subunit Ndufs4 is knocked out (KO). In patient-derived fibroblasts, NAD+ levels did not differ significantly from those of healthy controls (p = 0.79); however, NADH levels were significantly elevated (p = 0.04), indicating increased NADH reductive stress. This increase, observed despite comparable total NAD(H) levels between the groups, was attributed to elevated NADH levels. Similarly, in the mouse model, NADH levels were significantly increased in the KO group (p = 0.002), further suggesting that NADH elevation drives reductive stress. This precise method for NADH measurement is expected to outperform conventional assays, such as those for lactate, providing a simpler and more reliable means of assessing disease progression.

Keywords:  LC-MS/MS; Leigh syndrome; NADH; Ndufs4-KO mice; mitochondrial diseases; reductive stress

DOI:  https://doi.org/10.3390/biom15010038
Heliyon. 2025 Jan 15. 11(1): e41592

The landscape of rare mitochondrial DNA variants in sudden cardiac death: A potential role for ATP synthase.

Elena Luppi, Monica De Luise, Carla Bini, Guido Pelletti, Gaia Tioli, Ivana Kurelac, Luisa Iommarini, Susi Pelotti, Giuseppe Gasparre.

  Sudden cardiac death (SCD) is a major health concern, which can be the sign of a latent mitochondrial disease. However, mitochondrial DNA (mtDNA) contribution is largely unexplored in SCD at population level. Recently, mtDNA variants have been associated with congenital cardiopathy and higher risk of ischemic heart disease, suggesting them as potential risk factors also in SCD. Therefore, we aimed to define the mtDNA mutational landscape in such phenotype, by sequencing the whole blood mtDNA genome in a pilot cohort of 28 unrelated subjects. Coding variants were prioritized according to their population and haplogroup frequency. Out of 28 patients, 36% were diagnosed with coronary artery disease, 39% with structural defects and 25% with unspecified cardiac disease. The overall frequency of macro-haplogroups followed the distribution in the European population. No known or novel mtDNA pathogenic variants were found. Two rRNA and 8 missense variants were rarer than polymorphisms as they had a frequency lower than 1% in population databases. 5/8 missense variants clustered in ATP synthase genes and 4/8 missense variants were previously detected in patients with suspected mitochondriopathy. We concluded that primary mitochondrial disease is not a major cause of SCD, but rare mtDNA variants may occur (35.7% in our cohort vs 0.65% in the population; p < 0.01), potentially modifying the risk.

Keywords:  Heart disease; M chromosome; Mitochondrial genome; Mitochondrial haplogroups; SNVs; Sudden cardiac death

DOI:  https://doi.org/10.1016/j.heliyon.2024.e41592
Sci Transl Med. 2025 Jan 29. 17(783): eadr0792

Correcting a pathogenic mitochondrial DNA mutation by base editing in mice.

Jose D Barrera-Paez, Sandra R Bacman, Till Balla, Derek Van Booven, Durga P Gannamedi, James B Stewart, Beverly Mok, David R Liu, David B Lombard, Anthony J Griswold, Danny D Nedialkova, Carlos T Moraes.

Primary mitochondrial disorders are most often caused by deleterious mutations in the mitochondrial DNA (mtDNA). Here, we used a mitochondrial DddA-derived cytosine base editor (DdCBE) to introduce a compensatory edit in a mouse model that carries the pathological mutation in the mitochondrial transfer RNA (tRNA) alanine (mt-tRNAAla) gene. Because the original m.5024C→T mutation (G→A in the mt-tRNAAla) destabilizes the mt-tRNAAla aminoacyl stem, we designed a compensatory m.5081G→A edit (C→T in the mt-tRNAAla) that could restore the secondary structure of the tRNAAla aminoacyl stem. For this, the DdCBE gene construct was initially tested in an m.5024C→T mutant cell line. The reduced mt-tRNAAla amounts in these cells were increased after editing up to 78% of the mtDNA. Then, DdCBE was packaged in recombinant adeno-associated virus 9 (AAV9) and intravenously administered by retro-orbital injections into mice. Expression of the transduced DdCBE was observed in the heart and skeletal muscle. Total mt-tRNAAla amounts were restored in heart and muscle by the m.5081G→A edit in a dose-dependent manner. Lactate amounts, which were increased in the heart, were also decreased in treated mice. However, the highest dose tested of AAV9-DdCBE also induced severe adverse effects in vivo because of the extensive mtDNA off-target editing that it generated. These results show that although DdCBE is a promising gene therapy tool for mitochondrial disorders, the doses of the therapeutic constructs must be carefully monitored to avoid deleterious off-target editing.

DOI: https://doi.org/10.1126/scitranslmed.adr0792
Mol Genet Metab. 2025 Jan 20. pii: S1096-7192(25)00014-9. [Epub ahead of print]144(3): 109023

Comprehensive analysis of GDF15 as a biomarker in primary mitochondrial myopathies.

Paloma Martín-Jimenez, Laura Bermejo-Guerrero, María Navarro-Riquelme, Pablo Serrano-Lorenzo, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, David Lora, Montserrat Morales, Joaquín Arenas, Alberto Blázquez, Miguel Ángel Martín, Cristina Domínguez-González.

   BACKGROUND AND OBJECTIVES: Mitochondrial diseases are caused by defects in oxidative phosphorylation, with primary mitochondrial myopathies (PMM) being a subset where muscle involvement is predominant. PMM presents symptoms ranging from exercise intolerance to progressive muscle weakness, often involving ocular muscles, leading to ptosis and progressive external ophthalmoplegia (PEO). PMM can be due to variants in mitochondrial or nuclear DNA. Growth differentiation factor 15 (GDF15) has been identified as an accurate biomarker for mitochondrial dysfunction. This study evaluates the utility of GDF15 as a biomarker for monitoring PMM.
METHODS: This observational study involved 50 adult PMM patients. Clinical data were collected alongside functional motor outcomes measured by the Motor Research Council scale, 6-min walk test, North Star Ambulatory Assessment, and 100-m run test (100MRT). Biomarkers including serum lactate, creatine kinase (CK), creatinine, and plasma GDF15 were assessed.
RESULTS: Patients exhibited diverse phenotypes, including exercise intolerance (8 %), progressive myopathy (22 %), isolated PEO (24 %), and PEO plus (42 %). Significant correlations were found among motor function tests, with 100MRT being particularly sensitive. Biomarker analysis showed elevated lactate in 32 %, elevated CK in 54 %, reduced creatinine in 76 %, and elevated GDF15 in 86 % of cases. GDF15 levels correlated with motor performance, lactate levels, and mtDNA mutation load in muscle. Creatinine levels were strongly linked to disease severity.
DISCUSSION: This study underscores the heterogeneity of PMM and the importance of reliable biomarkers. GDF15 was consistently elevated across all PMM phenotypes and genotypes, correlating well with disease severity. Reduced creatinine also emerged as a potential prognostic marker.

Keywords:  Biomarker; GDF15; Mitochondrial disease; Natural history; Primary mitochondrial myopathy

DOI:  https://doi.org/10.1016/j.ymgme.2025.109023
Int J Mol Sci. 2025 Jan 13. pii: 626. [Epub ahead of print]26(2):

Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases.

Raya Kh Yashooa, Elisa Duranti, Donatella Conconi, Marialuisa Lavitrano, Suhad A Mustafa, Chiara Villa.

  MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.

Keywords:  microRNAs; mitochondria; neurodegenerative disorders

DOI:  https://doi.org/10.3390/ijms26020626
Value Health. 2025 Jan 27. pii: S1098-3015(25)00026-9. [Epub ahead of print]

Rare Disease Policy in High-Income Countries: An Overview of Achievements, Challenges, and Solutions.

Arianna Gentilini, Emilie Neez, Durhane Wong-Rieger.

   OBJECTIVES: To provide an overview of policy initiatives in high-income countries aimed at supporting the development and accessibility of treatments for rare diseases.
METHODS: We examine how legislative, research, and pricing policies in high-income countries address barriers that have historically hindered innovation and access to rare disease treatments. By analysing examples from the EU, UK, US, Canada, Japan, and Australia, the article identifies ongoing initiatives, outlines current challenges, and explores proposed solutions to foster a sustainable, innovative, and accessible rare disease treatment ecosystem.
RESULTS: The review highlights policies like legislative incentives in the EU, US, and Japan for orphan drug development, public-private partnerships to boost innovation, and patient registries to support research and clinical trials. Despite these efforts, major challenges persist, including high therapy costs, limited access to innovation for ultra-rare diseases, and diagnostic delays, with significant disparities across regions.
CONCLUSIONS: Overcoming these challenges will require sustainable pricing and reimbursement frameworks, alongside stronger collaboration between stakeholders, particularly for ultra-rare diseases. Advanced technologies like AI hold promise for improving diagnostic accuracy and data collection, supported by enhanced coding systems and registries to facilitate more robust research.

Keywords:  Orphan drugs; Pricing & reimbursement; R&D; Rare disease policy

DOI:  https://doi.org/10.1016/j.jval.2024.12.009
Life Med. 2024 Apr;3(2): lnae017

Mitochondrial transplantation for the treatment of cardiac and noncardiac diseases: mechanisms, prospective, and challenges.

Xinyi Wang, Zhiyuan Liu, Ling Zhang, Guangyu Hu, Ling Tao, Fuyang Zhang.

  Mitochondrial transplantation (MT) is a promising therapeutic strategy that involves introducing healthy mitochondria into damaged tissues to restore cellular function. This approach has shown promise in treating cardiac diseases, such as ischemia-reperfusion injury, myocardial infarction, and heart failure, where mitochondrial dysfunction plays a crucial role. Transplanting healthy mitochondria into affected cardiac tissue has resulted in improved cardiac function, reduced infract size, and enhanced cell survival in preclinical studies. Beyond cardiac applications, MT is also being explored for its potential to address various noncardiac diseases, including stroke, infertility, and genetic mitochondrial disorders. Ongoing research focused on refining techniques for mitochondrial isolation, preservation, and targeted delivery is bolstering the prospects of MT as a clinical therapy. As the scientific community gains a deeper understanding of mitochondrial dynamics and pathology, the development of MT as a clinical therapy holds significant promise. This review provides an overview of recent research on MT and discusses the methodologies involved, including sources, isolation, delivery, internalization, and distribution of mitochondria. Additionally, it explores the effects of MT and potential mechanisms in cardiac diseases, as well as non-cardiac diseases. Future prospects for MT are also discussed.

Keywords:  cardiac diseases; heart; mitochondria; mitochondrial transplantation; noncardiac diseases

DOI:  https://doi.org/10.1093/lifemedi/lnae017
Cell Biosci. 2025 Jan 24. 15(1): 9

Mitochondrial base editing: from principle, optimization to application.

Jinling Tang, Kunzhao Du.

  In recent years, mitochondrial DNA (mtDNA) base editing systems have emerged as bioengineering tools. DddA-derived cytosine base editors (DdCBEs) have been developed to specifically induce C-to-T conversion in mtDNA by the fusion of sequence-programmable transcription activator-like effector nucleases (TALENs) or zinc-finger nucleases (ZFNs), and split deaminase derived from interbacterial toxins. Similar to DdCBEs, mtDNA adenine base editors have been developed with the ability to introduce targeted A-to-G conversions into human mtDNA. In this review, we summarize the principles of mtDNA base-editing systems and elaborate on the evolution of different platforms of mtDNA base editors, including their deaminase replacement, engineering of DddAtox variants, structure optimization and editing outcomes. Finally, we highlight their applications in animal models and human embroys and discuss the future developmental direction and challenges of mtDNA base editors.

Keywords:  DdCBEs; Genetic engineering; Mitochondrial DNA; TALENs; mtDNA base editing

DOI:  https://doi.org/10.1186/s13578-025-01351-8
J Pediatr. 2025 Jan 24. pii: S0022-3476(25)00018-6. [Epub ahead of print] 114478

Ethical Challenges in Pediatric Medical Complexity: A Survey of Parents.

Miriam C Shapiro, Kathryn Detwiler, Jennifer Shepard, Talia Bernhard, Xiaobai Li, Renee D Boss, Vanessa N Madrigal.

   OBJECTIVE: To understand parents' experiences of ethical challenges in the care of children with chronic and serious medical conditions and what resources they access for support.
STUDY DESIGN: We recruited English-speaking parents of children with complex and serious medical conditions via family advocacy groups to complete an electronic survey from October 2022 through February 2023. We queried respondents' experiences with specific ethical challenges in the care of their child, whether their concerns persisted, and what resources they accessed. Respondents also reported demographics, educational backgrounds, financial resources, and their child's medical needs.
RESULTS: 218 parents completed surveys. Parents reported experiencing each of the 15 presented ethical challenges with varying frequency. More than half of parents reported residual distress in 6/15 ethical challenges. Demographic variables (gender, relationship status, time since medical challenge, and ethnicity) were not associated with level of distress related to ethical challenges. When facing challenges, respondents most commonly communicated with family members, friends, doctors, and other parents of children with medical problems, accessed the internet, and relied on their instincts or prayer/meditation.
CONCLUSIONS: Parents of children with medical complexity experience ethical challenges in the care of their children, although covering a broader range of experiences than typically considered by clinicians to have ethical dimensions. Many of these challenges leave residual distress. The resources that families report accessing to navigate these challenges are ones that typically do not have training, background, or specificity to medical ethics.

Keywords:  Children with medical complexity; bioethics; decision-making

DOI:  https://doi.org/10.1016/j.jpeds.2025.114478
J Comp Eff Res. 2025 Jan 30. e240050

The impact of a patient advisory board on a clinical comparative effectiveness trial: a comparison of patient and researcher perspectives.

Laura M Kernan, Monica Baczko Pearl, Adina Harri, Carol A Lambourne, Robert Schlegel, C McCollister Evarts, Mary Beth Crummer, Conrad Persels, Nancy Mullen, Vincent D Pellegrini.

  Aim: To examine contributions of a patient advisory board (PAB) to the design and conduct of The Pulmonary Embolism Prevention after Hip and Knee Replacement (PEPPER) Trial (NCT02810704) and compare perceptions of PAB members and researchers on the Trial. Materials & methods This evaluation of the PAB was conducted by Clinical Coordinating Center (CCC) members who first discussed PAB contributions, leading to the design of a semi-structured WebEx interview individually querying PAB members on their experience. Two study team members analyzed transcriptions of the interviews for common themes, which were discussed and affirmed at an in-person meeting with PAB members. Results: The contribution most frequently cited as meaningful by PAB members was the creation of a recruitment video. In contrast, the research team considered the most impactful PAB recommendation to be omission of pneumatic compression boots as a study variable. PAB members spoke highly of their involvement in the trial and emphasized shared decision-making in the patient-physician relationship. Conclusion: Researchers and PAB members had different opinions about which PAB contributions were most impactful to the study. This likely derives from differences in perspective; PAB members focused on patient experience and the patient-surgeon relationship while researchers focused primarily on trial outcomes. PAB contributions led to two major protocol changes that had a substantial positive effect on trial design, recruitment and enrollment. This evaluation adds to the engagement literature, which contains little on what patients think of their involvement in the design and conduct of clinical research studies and will aid in encouraging treatment preference discussions between patient and surgeon, thereby supporting the goal of improved patient outcomes.

Keywords:  clinical trial design; comparative effectiveness research; patient advisory body; patient empowerment; patient engagement; patient involvement in research; shared decision-making; stakeholder engagement

DOI:  https://doi.org/10.57264/cer-2024-0050