bims-curels 2025-06-22 papers

Issue of 2025–06–22
seven papers selected by
Cure Mito Foundation

J Neuromuscul Dis. 2025 Jun 19. 22143602241307198

Modelling mitochondrial diseases in neurons In Vitro: A systematic review.

Mariana Zarate-Mendez, Nihal A Basha, Oliver Podmanicky, Natalia Malig, Denisa Hathazi, Rita Horvath.

Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.

Keywords: induced pluripotent stem cells; neuronal models; primary mitochondrial diseases

DOI: https://doi.org/10.1177/22143602241307198

Mitochondrion. 2025 Jun 18. pii: S1567-7249(25)00058-3. [Epub ahead of print] 102061

Machine learning to predict mitochondrial diseases by phenotypes.

Chieh-Wen Kuo, Hui-An Chen, Rai-Hseng Hsu, Chaoszu Wu, Ching Hsu, Ming-Jen Lee, Yin-Hsiu Chien, Hsueh-Wen Hsueh, Feng-Jung Yang, Pi-Chuan Fan, Wen-Chin Weng, Ru-Jen Lin, Ta-Ching Chen, Chih-Chao Yang, Wang-Tso Lee, Wuh-Liang Hwu, Ni-Chung Lee.

Diagnosing mitochondrial diseases remains challenging because of the heterogeneous symptoms. This study aims to use machine learning to predict mitochondrial diseases from phenotypes to reduce genetic testing costs. This study included patients who underwent whole exome or mitochondrial genome sequencing for suspected mitochondrial diseases. Clinical phenotypes were coded, and machine learning models (support vector machine, random forest, multilayer perceptron, and XGBoost) were developed to classify patients. Of 103 patients, 43 (41.7%) had mitochondrial diseases. Myopathy and respiratory failure differed significantly between the two groups. XGBoost achieved the highest accuracy (67.5%). In conclusion, machine learning improves patient prioritization and diagnostic yield.

Keywords: Machine learning; Mitochondrial diseases; Phenotype

DOI: https://doi.org/10.1016/j.mito.2025.102061

Orphanet J Rare Dis. 2025 Jun 13. 20(1): 306

The m.3290T > C variant might be a protective factor against the pathogenic m.3243 A > G variant: a case study.

Ning Zhang, Zhikang Zhang, Ying Zhang, Xun Su, Yuzhou Gao, Jing Yang, Weiwei Zou, Dongmei Ji, Yunxia Cao.

The mitochondrial m.3243 A > G variant is a prevalent mitochondrial disease mutation that causes multisystem maternal inheritance disorders. While clinical severity typically correlates with mutation load, symptom manifestation may be influenced by other variants and environmental factors. Notably, the m.3290T > C variant has been hypothesized as a potential protective variant for m.3243 A > G pathogenicity, though clinical evidence remains limited. Here we reported a six-generation Chinese pedigree carrying both m.3243 A > G and homoplasmic m.3290T > C variants. Clinical and genetic analyses revealed that carriers with extremely high m.3243 A > G heteroplasmy (> 95%) exhibited severe symptoms, whereas those with moderate or high levels showed limited or no clinical symptoms. Our findings provide novel evidence for the protective role of m.3290T > C in mitigating m.3243 A > G pathogenicity, highlighting its potential clinical significance.

Keywords: MELAS; Mitochondrial DNA; Mitochondrial disease; m.3243A > G; m.3290T > C

DOI: https://doi.org/10.1186/s13023-025-03774-5

Sci Rep. 2025 Jun 19. 15(1): 18717

Lipid nanoparticle delivery of the CRISPR/Cas9 system directly into the mitochondria of cells carrying m.7778G>T mutation in MtDNA (mt-Atp8).

Kaede Norota, Sen Ishizuka, Misa Hirose, Yusuke Sato, Masatoshi Maeki, Manabu Tokeshi, Saleh M Ibrahim, Hideyoshi Harashima, Yuma Yamada.

Mitochondrial genome mutations are associated with various diseases and gene therapy targeted to mitochondria has the potential to effectively treat such diseases. Here, we targeted a point mutation in mitochondrial DNA (mtDNA) that can cause mitochondrial diseases via delivery of the clustered, regularly interspaced, short palindromic repeats/Cas9 (CRISPR/Cas9) system to mitochondria using an innovative lipid nanoparticle (LNP) delivery system. To overcome the major barrier of the mitochondrial membrane structure, we investigated a strategy to deliver ribonucleoprotein (RNP) directly to mitochondria via membrane fusion using MITO-Porter, a mitochondria-targeting lipid nanoparticle. First, we constructed RNP-MITO-Porter, in which an RNP was loaded into MITO-Porter using a microfluidic device. Sequence-specific double-strand breaks were confirmed when the constructed RNP-MITO-Porter was applied to isolated mitochondria. Next, the RNP-MITO-Porter was applied to HeLa cells, and a portion of the RNP-MITO-Porter was colocalized with mitochondria and caused sequence-specific double-strand breaks in mtDNA. Finally, RNP-MITO-Porter was successfully delivered to mitochondria of cells derived from a mouse carrying a point mutation (m.7778G > T) in mtDNA (mt-Atp8) (LMSF-N-MTFVB cells), and created double-strand breaks at the target sequence. RNP-MITO-Porter is expected to contribute significantly to the clinical application of mitochondrion-targeted gene therapy.

Keywords: CRISPR/Cas9 ribonucleoprotein (RNP); Lipid nanoparticle (LNP); MITO-Porter; Mitochondrial genome editing; Mitochondrial-targeted delivery

DOI: https://doi.org/10.1038/s41598-025-03671-8

Mol Biomed. 2025 Jun 19. 6(1): 42

Role of mitochondria in physiological activities, diseases, and therapy.

Lilin Wang, Xiaoting Zhou, Tianqi Lu.

Mitochondria are generally considered essential for life in eukaryotic organisms because they produce most of the energy or adenosine triphosphate (ATP) needed by the cell. Beyond energy production, it is now widely accepted that mitochondria also play a pivotal role in maintaining cellular homeostasis and signaling. The two core processes of mitochondrial dynamics, fission and fusion, serve as crucial foundations for maintaining mitochondrial morphology, distribution, and quantity, thereby ensuring cellular homeostasis. Mitochondrial autophagy (mitophagy) ensures the selective degradation of damaged mitochondria, maintaining quality control. Mitochondrial transport and communication further enhance their role in cellular processes. In addition, mitochondria are susceptible to damage, resulting in dysfunction and disruption of intracellular homeostasis, which is closely associated with the development of numerous diseases. These include mitochondrial diseases, neurodegenerative diseases, cardiovascular diseases (CVDs) and stroke, metabolic disorders such as diabetes mellitus, cancer, infectious diseases, and the aging process. Given the central role of mitochondria in disease pathology, there is a growing need to understand their mechanisms and develop targeted therapies. This review aims to provide a comprehensive overview of mitochondrial structure and functions, with a particular focus on their roles in disease development and the current therapeutic strategies targeting mitochondria. These strategies include mitochondrial-targeted antioxidants, modulation of mitochondrial dynamics and quality control, mitochondrial genome editing and genetic therapy, and mitochondrial transplantation. We also discuss the challenges currently facing mitochondrial research and highlight potential future directions for development. By summarizing the latest advancements and addressing gaps in knowledge, this review seeks to guide future research and clinical efforts in the field of mitochondrial medicine.

Keywords: Cancer; Mitochondria; Mitochondrial diseases; Mitochondrial homeostasis; Therapy

DOI: https://doi.org/10.1186/s43556-025-00284-5

Res Involv Engagem. 2025 Jun 17. 11(1): 65

The ultimate power play in research - partnering with patients, partnering with power.

Dawn P Richards, Janelle Bowden, Patrick Gee, Alex Haagaard, Anita Kothari, Annette McKinnon, Codie A Primeau, Andrea C Tricco, Ellen Wang, Karen L Woolley, Linda C Li.

BACKGROUND: Patient and public involvement (PPI), also called patient engagement, patient partnership, or consumer involvement, holds potential to change approaches and outcomes in research and healthcare. All research teams have complex power dynamics, including those with patient/public members. We present our perceptions and understandings of power arising from our own experiences on health research teams. We suggest ways for members of health research teams to move forward in efforts to minimize power discrepancies.
MAIN BODY: As an international group of patients, caregivers, and research allies, we have experienced power dynamics within PPI collaborations and believe they must be challenged to achieve more equitable partnerships. We explore four themes relating to power in no order of importance: (1) The unstable and changing nature of power in PPI. Patient/public partners' abilities and capacities to engage equally depend on the working environment and on their economic, cultural, social and symbolic (including health) capitals; (2) Power between and amongst patients/public partners. Layers of power exist between and amongst patient/public partners and their networks, which may lead to a lack of diversity in partners and/or bullying and requires recognizing that not all patient/public partners bring the same experiences, skills or perspectives to research teams; (3) Power and tokenism. Tokenism occurs when patient/public perspectives in PPI are mostly ignored, results when power and resources are disproportionately concentrated, and can be perpetuated by funding and funding agency infrastructures; and, (4) PPI as a commodity or product. PPI may be seen or used as a means to extract experiences or validate one's work without truly involving patients/public contributors in the research design and process. PPI aligns with a broader trend of academic research methodologies grounded in standpoint epistemology (that is, how a person's social identity influences what they know). We include practical recommendations for researchers and for patient/public partners to share power more equitably on research teams.
CONCLUSION: In our experiences on health research teams, patient/public partners are often the most vulnerable and most disadvantaged members of the team who experience the largest power inequities. We hope our identified themes about power, the context related to power, and our reflections and recommendations on them inspire those holding power on research teams to share that power.

Keywords: And inclusion; Co-production; Consumer involvement; Diversity; Equity; Patient and public involvement; Patient engagement; Patient partnership; Power; Power dynamics; Power imbalance; Research

DOI: https://doi.org/10.1186/s40900-025-00745-9

Ther Innov Regul Sci. 2025 Jun 20.

Opportunities in Development of Patient-Centric and Decentralized Clinical Trials: Insights from Patients and Healthcare Professionals in Respiratory and Rare Diseases.

Marisa Minetti, Eva Topole, Ilaria Rondinone, Marta Lombardini, Paola Kruger, Mario Picozza, Simona Barbaglia, Andrea Terenzi, Ian Culverhouse, Lisa Forde, Isabella Montagna, Ylenia Paleari.

BACKGROUND: Decentralized clinical trials (DCTs) are increasingly being used to enable greater participation of patients in clinical research and improve the patient experience. In 2021, the Chiesi research and development team established the Digital innovAtion for patieNt Centric hEalth (DANCE) initiative with the aim to enhance the clinical trial journey for participants by merging patient perspectives with modern technology. As part of this project, the concept of DCTs was explored with patients affected by respiratory or rare diseases and with healthcare professionals (HCPs) treating these patients in the USA and Europe.
METHODS: The concept of the clinical trial journey and DCTs were initially explored through semi-structured interviews with 37 patients and HCPs. A follow-on web survey of 390 patients and HCP participants was then performed to gather opinions on the different components of DCTs and to identify elements to be incorporated in future DCTs. A final web survey with 135 patients and caregivers expanded on the DCT concept focusing on direct-to-patient delivery of investigational medications.
RESULTS: Overall, both patients and HCPs liked and were open to the concept of DCTs. They believed this approach in clinical trials would avoid patients having to travel long distances for screening or study visits, and increase participation of diverse populations in trials. The main concerns for both patients and HCP participants were the reduction of face-to-face interactions and whether the technology would be easy to use.
CONCLUSIONS: This work highlights the benefits of DCTs and identifies potential challenges to be addressed to make DCTs more appealing to all participants. Responses also demonstrate the significance of integrating face-to-face contact with remote contact through user-friendly tools.

Keywords: Decentralized clinical trial; Direct-to-patient delivery; Patient perspective; Patient-centric; Qualitative study; Rare disease; Respiratory disease

DOI: https://doi.org/10.1007/s43441-025-00819-6