bims-curels 2025-06-29 papers

Issue of 2025–06–29
six papers selected by
Cure Mito Foundation

PLoS Biol. 2025 Jun;23(6): e3003207

Correction of pathogenic mitochondrial DNA in patient-derived disease models using mitochondrial base editors.

Indi P Joore, Sawsan Shehata, Irena Muffels, Jose Castro-Alpízar, Elena Jiménez-Curiel, Emilia Nagyova, Natacha Levy, Ziqin Tang, Kimberly Smit, Wilbert P Vermeij, Richard Rodenburg, Raymond Schiffelers, Edward E S Nieuwenhuis, Peter M van Hasselt, Sabine A Fuchs, Martijn A J Koppens.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

DOI: https://doi.org/10.1371/journal.pbio.3003207

J Biochem. 2025 Jun 20. pii: mvaf037. [Epub ahead of print]

Mitochondrial DNA: leakage, recognition, and associated human diseases.

Hyota Takamatsu.

Mitochondria are intracellular organelles originating from intracellular symbiotic bacteria that play essential roles in life activities such as energy production, metabolism, Ca2+ storage, signal transduction, and cell death. Mitochondria also function as hubs for host defense against harmful stimuli such as infection and inflammation control. However, when cells are exposed to stress, mitochondrial homeostasis is disrupted, and mitochondrial DNA (mtDNA) can leak into the cytoplasm or extracellular space. Leaked mtDNA activates innate immune sensors, causing severe inflammation and contributing to the pathogenesis of human diseases. In this review, we summarize the mechanisms by which mtDNA leaks from the mitochondria and subsequently induces inflammation. We also review the relationship between mtDNA leakage and human diseases.

Keywords: human diseases; innate immune response; mitochondria quality control; mitochondrial DNA; mtDNA leakage

DOI: https://doi.org/10.1093/jb/mvaf037

Nat Aging. 2025 Jun 27.

Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.

Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang.

Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.

DOI: https://doi.org/10.1038/s43587-025-00909-y

bioRxiv. 2025 May 03. pii: 2025.04.29.650984. [Epub ahead of print]

Replication competition drives the selective mtDNA inheritance in Drosophila ovary.

Cheng Zhang, Zhe Chen, Hansong Ma, Hong Xu.

Purifying selection that limits the transmission of harmful mitochondrial DNA (mtDNA) mutations has been observed in both human and animal models. Yet the precise mechanism underlying this process remains undefined. Here, we present a highly specific and efficient in situ imaging method capable of visualizing mtDNA variants that differ by only a few nucleotides at single-molecule resolution in Drosophila ovaries. Using this method, we revealed that selection primarily occurs within a narrow developmental window during germline cysts differentiation. At this stage, the proportion of the deleterious mtDNA variant decreases without a reduction in its absolute copy number. Instead, the healthier mtDNA variant replicates more frequently, thereby outcompeting the co-existing deleterious variant. These findings provide direct evidence that mtDNA selection is driven by replication competition rather than active elimination processes, shedding light on a fundamental yet previously unresolved mechanism governing mitochondrial genome transmission.

DOI: https://doi.org/10.1101/2025.04.29.650984

Front Cardiovasc Med. 2025 ;12 1582219

Mitochondrial DNA depletion syndrome and its cardiac complication.

Shengfang Bao, Jiajun Ye, Jiaqi Zhou, Chen Zheng, Yuejuan Xu, Sun Chen.

Mitochondrial depletion syndrome (MTDPS) is a heterogeneous group of genetic disorders characterized by a significant reduction in mitochondrial DNA (mtDNA) copy number, leading to the impaired mitochondrial function. The pathogenesis of MTDPS includes impaired mtDNA replication, damaged nucleotide metabolism and dysregulated mitochondrial dynamics. Due to its high energy demands, the heart is sensitive to the mitochondrial dysfunction. And the energy deficiency caused by the MTDPS contributes to the development of the mitochondrial cardiomyopathy. In this review, we summarize the cardiac phenotypes in the MTDPS, and the role of the mitochondrial injury in the myocardial damage. In specific, the association of the MTDPS-causing genes and their cardiac phenotypes are detailed. Moreover, the current treatment strategies for MTDPS are summarized. This review aims to integrate the current knowledge on the MTDPS and its cardiac phenotypes in order to provide insights for the further research and the clinic management.

Keywords: cardiomyopathy; mitochondrial DNA depletion syndrome; mitochondrial damage; mitochondrial dynamics; mitochondrial dysfunction; mtDNA replication; nucleotide metabolism

DOI: https://doi.org/10.3389/fcvm.2025.1582219

J Med Internet Res. 2025 Jun 27. 27 e68458

Empowering Capabilities of People With Chronic Conditions Supported by Digital Health Technologies: Scoping Review.

Messaline Fomo, Liyousew G Borga, Thomas Abel, Philip S Santangelo, Sara Riggare, Jochen Klucken, Ivana Paccoud.

BACKGROUND: Patient empowerment is widely recognized for improving health outcomes, increasing patient satisfaction, and enhancing the overall effectiveness of health care. Digital health technologies (DHTs) contribute to this empowerment by keeping patients informed, involved, and engaged in their own health. However, more evidence is needed to better understand which aspects of empowerment patients value when using DHTs and how DHTs can support these values.
OBJECTIVE: Drawing on Sen's capability approach, this paper conceptualizes patient empowerment in digital health by defining distinct capabilities, resources, and conversion factors that contribute to patient empowerment through DHTs.
METHODS: We based our scoping review on the methodology recommended by the Joanna Briggs Institute Manual for evidence synthesis and an a priori registered protocol. Papers were included if they focused on patient empowerment in relation to DHTs among patients with chronic diseases (cardiovascular diseases, diabetes, cancer, chronic respiratory diseases, and neurodegenerative diseases), with particular emphasis on the patient perspective. PubMed, Scopus, and Web of Science were searched for evidence published from January 2013 to April 2024. Data were extracted and thematically analyzed via a multidisciplinary workshop to identify empowerment components relevant to the capability framework, such as capabilities, DHTs as resources, and conversion factors.
RESULTS: Our analysis identified 3 core capabilities to achieve patient empowerment supported by DHTs: health information and knowledge management, self-management, and emotional and social support. DHTs as resources supported these capabilities through distinct functional components, including informing patients, communication with the health care team, monitoring, behavior change interventions, individualized feedback, or peer support, each contributing to a varying degree. Conversion factors such as demographic and socioeconomic status, digital literacy, disease status, perceived value of DHTs, sociocultural values and norms, doctor-patient relationship, connectivity, and cost influenced the development of empowering capabilities resulting from using DHTs.
CONCLUSIONS: While the capabilities related to patient empowerment in DHTs were clearly distinguishable, our analysis revealed a notable interconnectedness among these components. Our conceptualization of patient empowerment serves as a valuable resource for researchers seeking to understand or assess patient empowerment via DHTs. It also provides guidance for DHT developers, helping them design DHTs that enhance valued capabilities and account for the conversion factors and ultimately promote patient empowerment across diverse population groups.

Keywords: capability approach; chronic diseases; digital health; digital health technology; patient empowerment

DOI: https://doi.org/10.2196/68458