bims-curels 2024-07-28 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024‒07‒28
twelve papers selected by
Cure Mito Foundation

Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.
Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.
Early cardiac mechanics abnormalities in patients with mitochondrial diseases.
The three-parent baby: Medicolegal, forensic and ethical concerns.
Rare disease 101: an online resource teaching on over 7000 rare diseases in one short course.
The establishment of a molecular diagnostic platform for mitochondrial diseases: from conventional to next-generation sequencing.
An auto-ethnographic study of co-produced health research in a patient organisation: unpacking the good, the bad, and the unspoken.
Liver transplantation for mitochondrial DNA depletion syndrome caused by MPV17 deficiency: a case report and literature review.
A Comprehensive Framework for Evaluating the Value Created by Real-World Evidence for Diverse Stakeholders: The Case for Coordinated Registry Networks.
What Do We Mean by Sharing of Patient Data? DaSH - A Data Sharing Hierarchy of Privacy and Ethical Challenges.
Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
Mitochondrial DNA mosaicism in normal human somatic cells.

J Inherit Metab Dis. 2024 Jul 25.

Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.

Kristýna Čunátová, Erika Fernández-Vizarra.

  Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.

Keywords:  complex III assembly; complex III deficiency; mitochondrial disease; nuclear gene pathogenic variants; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.1002/jimd.12751
Genes (Basel). 2024 Jul 08. pii: 894. [Epub ahead of print]15(7):

Mechanisms and Future Research Perspectives on Mitochondrial Diseases Associated with Isoleucyl-tRNA Synthetase Gene Mutations.

Masaki Watanabe, Nobuya Sasaki.

  Aminoacyl-tRNA synthetases are essential enzymes for the accurate translation of genetic information. IARS1 and IARS2 are isoleucyl-tRNA synthetases functioning in the cytoplasm and mitochondria, respectively, with genetic mutations in these enzymes causing diverse clinical phenotypes in specific organs and tissues. Mutations in IARS1 and IARS2 have recently been linked to mitochondrial diseases. This review aims to explore the relationship between IARS1 and IARS2 and these diseases, providing a comprehensive overview of their association with mitochondrial diseases. Mutations in IARS1 cause weak calf syndrome in cattle and mitochondrial diseases in humans, leading to growth retardation and liver dysfunction. Mutations in IARS2 are associated with Leigh syndrome, craniosynostosis and abnormal genitalia syndrome. Future research is expected to involve genetic analysis of a larger number of patients, identifying new mutations in IARS1 and IARS2, and elucidating their impact on mitochondrial function. Additionally, genetically modified mice and the corresponding phenotypic analysis will serve as powerful tools for understanding the functions of these gene products and unraveling disease mechanisms. This will likely promote the development of new therapies and preventive measures.

Keywords:  IARS1; IARS2; aminoacyl-tRNA; mitochondrial disease

DOI:  https://doi.org/10.3390/genes15070894
Mitochondrion. 2024 Jul 22. pii: S1567-7249(24)00098-9. [Epub ahead of print] 101940

Early cardiac mechanics abnormalities in patients with mitochondrial diseases.

Rosa Lillo, Maria Chiara Meucci, Silvia Malara, Guido Primiano, Serenella Servidei, Antonella Lombardo, Maria Grandinetti, Massimo Massetti, Gaetano Antonio Lanza, Giuseppe Limongelli, Francesca Graziani.

  BACKGROUND: Evidence about early cardiac mechanics abnormalities in patients with mitochondrial diseases (MDs) before overt cardiomyopathy is limited METHODS: In this prospective study, we performed a comparative analysis of conventional and speckle tracking echocardiographic parameters between patients with genetically identified MDs and no overt cardiomyopathy vs controls matched for age, sex and cardiovascular risk factors. The Newcastle mitochondrial disease adult scale (NMDAS) was calculated, using a threshold of > 21 as indicator of high disease severity.RESULTS: We enrolled 24 MDs patients (50 % males, mean age 47.2 ± 14.3 years), the most prevalent mutation was the MT-TL1 m.3243A.G (37.5 %). In MDs patients all dimensional echocardiographic parameters were similar to controls. Conversely, albeit normal, Tissue Doppler septal systolic (p = 0.002) and early diastolic velocities (p = 0.016) were significantly lower and E/e' ratio was higher (p = 0.032) in MDs. Moreover, LV-GLS was significantly reduced in MDs as compared to their counterparties (20.2 ± 1.6 vs 22.6 ± 1.5, p < 0.001). Similarly, LA reservoir and conduit strain were significantly lower in MDs (31.7 ± 7.0 vs 35.9 ± 6.6, p = 0.038; 19.7 ± 5.6 vs 23.1 ± 6.0, p = 0.049 respectively), while LA contractile strain was similar between the two groups. Lower values of LV-GLS were observed in patients with NMDAS > 21 vs patients with NMDAS ≤ 21 (19.0 ± 1.2 vs 21.0 ± 1.3, p = 0.001).
CONCLUSIONS: In patients with MDs and no overt cardiomyopathy Tissue Doppler and speckle tracking analysis unveil worse LV systolic and diastolic function indices as compared to controls. Reduced LV-GLS values were found especially in those with worse disease burden.

Keywords:  Cardiac mechanics; Cardiomyopathy; Mitochondrial diseases; Speckle-tracking echocardiography; Strain

DOI:  https://doi.org/10.1016/j.mito.2024.101940
Med Sci Law. 2024 Jul 26. 258024241266566

The three-parent baby: Medicolegal, forensic and ethical concerns.

Nandini Chitara, Kewal Krishan, Tanuj Kanchan.

  In the recent past, human genetics and in vitro fertilization (IVF) have undergone various advances to combat with several congenital and developmental disorders. These advances are a boon for the families and patients who were restricted from having a child due to one or the other reasons. One such reason is the mitochondrial DNA (mtDNA) mutations, which are definitely transmitted from the mother to the child due to uniparental/maternal inheritance of mitochondria. Depending upon the range of the mutation (mutation loads) present, the mtDNA mutation leads to various devitalizing to fatal disorders, all of which are incurable. Scientists and researchers developed a technique known as mitochondrial donation technique or mitochondrial replacement therapy (MRT) to combat with the mtDNA mutations. The technique relies on the replacement of faulty mitochondria in the mother's egg with the normal wild-type from a donor female resulting in a "three-parent baby." On the other side, forensic scientists and anthropologists continuously explore the mtDNA in various medicolegal cases and in uncoupling the mystery of human origin and migration respectively. In this regard, we explored the genetic, forensic and ethical aspects of a "three-parent baby." The present communication also attempts to highlight the importance and limitations of the MRT technique/three-parent baby in a medicolegal context.

Keywords:  Mitochondrial DNA mutations; congenital disorder; medicolegal and forensic aspects; mitochondrial donation technique; three-parent baby

DOI:  https://doi.org/10.1177/00258024241266566
Orphanet J Rare Dis. 2024 Jul 22. 19(1): 275

Rare disease 101: an online resource teaching on over 7000 rare diseases in one short course.

Thomas Frederick Dunne, Daniel Jeffries, Lucy Mckay.

  BACKGROUND: An estimated 3.5 million people in the UK live with a rare disease however due to the rarity of each individual condition this is not currently reflected in mainstream medical education. As a result, common features of living with a rare condition include diagnostic delay, poor coordination of health and social care and lack of access to specialist care and treatment. This is well documented in reports published by patient advocacy groups collating the patient experience and has been highlighted by the Department of Health and Social Care in its UK Rare Diseases Framework. One of the four priority areas outlined in this policy published in 2021 is 'increasing awareness amongst healthcare professionals'. Medics4RareDiseases (M4RD), a charity based in the UK, has proposed a disease-agnostic approach to educating doctors about rare disease, focusing on the common challenges experienced across this heterogeneous collection of conditions, rather than on the minutiae of each of the > 7000 rare conditions. A literature search using MEDLINE, PubMed Central and Bookshelf confirmed a lack of broad rare disease teaching in medical literature; none of the 10 final resources identified focused on the topic as a whole.RESULTS: To address this, M4RD created the course 'Rare Disease 101'. It is accessed online using a learning management system that is free, contains interactive lessons, hosts a discussion board and is easily updated. In the 29 months since going live, 942 individuals have registered with 204 having completed the course; early feedback from 33 respondents was unanimously positive (all participants rated at least good (76%: excellent)) demonstrating that both clinicians and patients can benefit from broad rare disease education. The course is freely available to all at https://learn.m4rd.org/ .
CONCLUSIONS: Disease-agnostic training about rare disease as a large patient population, focusing on its unique profile of unmet needs, is required. Rare Disease 101 provides a pragmatic approach to an educational challenge that leads to poor patient outcomes. Early results suggest that the educational programme is well-received but further evaluation and assessment is needed.

Keywords:  Advocacy; Education; Genomics; Interactive learning; Learning management system; Online education; Patient experience; Patient expert; Rare disease

DOI:  https://doi.org/10.1186/s13023-024-03286-8
Biomed J. 2024 Jul 22. pii: S2319-4170(24)00073-8. [Epub ahead of print] 100770

The establishment of a molecular diagnostic platform for mitochondrial diseases: from conventional to next-generation sequencing.

Ni-Chin Tsai, Chai-Wai Liou, Yin-Hua Cheng, Hao-Ting Lien, Tzu-Ling Lin, Tsu-Kung Lin, Min-Yu Lan, Pi-Lien Hung, Tzu-Jou Wang, Chen-Hao Lee, Yi-Chih Liang, Kuo-Chung Lan.

  BACKGROUND: The aim of this study was to create a molecular diagnostic platform and establish a diagnostic pipeline for patients highly suspected of mitochondrial disorders. The effectiveness of three methods, namely, traditional restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR), Sanger sequencing for hotspot detection and whole mitochondrial DNA (mtDNA), and third-generation (Nanopore) whole mtDNA sequencing, will be compared in diagnosing patients with suspected primary mitochondrial diseases (PMDs). The strengths and limitations of different methods are also discussed.MATERIAL AND METHODS: A single-center prospective cohort study was conducted to validate the diagnostic pipeline for suspected mitochondrial diseases. In the first stage, a PCR-based method with five sets of primers was used to screen for eight hotspots (m.3243A>G, m.3460G>A, m.8344A>G, m.8993T>G, m.9185T>C, m.11778G>A, m.13513G>A, and m.4977deletion) using either RFLP or direct Sanger sequencing. Sanger sequencing was also used to confirm the RFLP-positive samples. In the second stage, for samples with negative screening results for the eight hotspots, mitochondrial whole-genome sequencing was performed using Sanger sequencing or third-generation nanopore sequencing.
RESULTS: Between June 2020 and May 2023, 30 patients from ages 0 to 63 with clinically suspected mitochondrial disease were enrolled. The positive yield for the diagnosis of PMDs was 8/30=26.7%, and the sensitivity of the heteroplasmy level for the RFLP-based method was approximately 5%. The remaining 22 patients who tested negative at the first stage were tested using Sanger sequencing or the third-generation sequencing Nanopore, and all tested negative for pathological mtDNA mutations. Compared to the Sanger sequencing method, the results of RFLP-PCR were compromised by the limitations of incomplete RFLP enzyme digestion. For whole-genome sequencing of mtDNA, Sanger sequencing, instead of nanopore sequencing, is preferred at our institution because of its cost-effectiveness.
CONCLUSIONS: In our highly selective cohort, most tested positive in the first stage of the 8 hot spots screen. Sanger sequencing is a conventional and accurate method for mitochondrial disease screening, at least for the most common hot spots in the region. The results revealed that Sanger sequencing is an accurate method with the benefit of being more cost-effective. This integral platform of molecular diagnosis bears the advantages of being relatively low cost and having a shorter reporting time, facilitating crucial identification of patients with clinical evidence of such disorders. This diagnostic flowchart has also been translated into routine clinical use in the tertiary hospital.

Keywords:  Mitochondrial DNA amplification; mitochondrial disease; molecular diagnostic platform; whole mitochondrial DNA sequencing

DOI:  https://doi.org/10.1016/j.bj.2024.100770
Res Involv Engagem. 2024 Jul 23. 10(1): 76

An auto-ethnographic study of co-produced health research in a patient organisation: unpacking the good, the bad, and the unspoken.

Astrid Janssens, Danielle Drachmann, Kristy Barnes-Cullen, Austin Carrigg, Henrik Thybo Christesen, Becky Futers, Yvette Ollada Lavery, Tiffany Palms, Jacob Sten Petersen, Pratik Shah, Paul Thornton, Joseph Wolfsdorf.

  BACKGROUND: In rare diseases, limited access to services and rare disease experts may force families to act as medical advocates for their child; they can volunteer to support clinician-initiated research or initiate and lead research themselves. Ketotic Hypoglycemia International (KHI) is a new, global organization for families affected by idiopathic ketotic hypoglycemia (IKH) and is run solely by volunteers. Doing research together, families and international experts in a collaborative process such as at KHI, also referred to as patient and public involvement and engagement (PPIE) or extreme citizen science, is often praised for its positive effects on the research and the stakeholders involved.METHODS: We used auto-ethnographic narratives from parents and medical professionals in KHI to report on their experiences with co-produced health research. All co-authors wrote down their experiences in relation to three topics: time invested, work invested and power dynamics.
RESULTS: Whilst the parents and health care professionals felt a new hope for (their) children with IKH, they also felt pressure to contribute time or to be flexible in how and when they dedicated time towards the organization. The power dynamics were characterised by a change in the relationship between the parents and medical experts; the parent being taught by the expert shifted to the expert learning from the lived experience of the parent. Both parents and medical experts struggled with maintaining boundaries and safeguarding their mental health.
CONCLUSION: Our findings call for the need to secure and prioritize funding for patient organizations, to enable them to create the sustainable architecture required for meaningful PPIE within these organizations. The morals and often deeply personal reasons for engaging with voluntary work in health research, can lead to overstepping of boundaries. As a result of our research, we call for the development of ethics of care guidelines within collaborative health research.

Keywords:  Auto-ethnography; Citizen science; Patient and public involvement and engagement; Patient organisation; Rare disease

DOI:  https://doi.org/10.1186/s40900-024-00609-8
Front Surg. 2024 ;11 1348806

Liver transplantation for mitochondrial DNA depletion syndrome caused by MPV17 deficiency: a case report and literature review.

Liu-Yuan Wei, Xiu-Qi Chen, Li Huang, Qing-Wen Shan, Qing Tang.

  Objective: To study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV17 gene variant.Case presentation: A boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate.
Conclusion: Hepatocerebral MDS patients without neurological symptoms may benefit from LT.

Keywords:  MPV17 gene; chidren; liver transplant; mitochondrial DNA depletion syndrome; mitochondrial disease

DOI:  https://doi.org/10.3389/fsurg.2024.1348806
Ther Innov Regul Sci. 2024 Jul 25.

A Comprehensive Framework for Evaluating the Value Created by Real-World Evidence for Diverse Stakeholders: The Case for Coordinated Registry Networks.

Laura Elisabeth Gressler, Danica Marinac-Dabic, Frederic S Resnic, Stuart Williams, Kevin Yang, Frank Weichold, Erika Avila-Tang, Christina Mack, Paul Coplan, Orestis A Panagiotou, Gregory Pappas.

  OBJECTIVES: This manuscript presents a comprehensive framework for the assessment of the value of real-world evidence (RWE) in healthcare decision-making. While RWE has been proposed to overcome some limitations of traditional, one-off studies, no systematic framework exists to measure if RWE actually lowers the burden. This framework aims to fill that gap by providing conceptual approaches for evaluating the time and cost efficiencies of RWE, thus guiding strategic investments in RWE infrastructure.METHODS: The framework consists of four components: (114th Congress. 21st Century Cures Act.; 2015. https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf .) identification of stakeholders using and producing RWE, (National Health Council. Glossary of Patient Engagement Terms. Published 2019. Accessed May 18. 2021. https://nationalhealthcouncil.org/glossary-of-patient-engagement-terms/ .) understanding value propositions on how RWE can benefit stakeholders, (Center for Drug Evaluation and Research. CDER Patient-Focused Drug Development. U.S. Food & Drug Administration.) defining key performance indicators (KPIs), and (U.S. Department of Health and Human Services - Food and Drug Administration: Center for Devices and Radiological Health and Center for Biologics Evaluation and Research. Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices - Guidance for Industry and Food and Drug Administration Staff. 2017. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida .) establishing metrics and case studies to assess value. KPIs are categorized as 'better, faster, or cheaper" as an indicator of value: better focusing on high-quality actionable evidence; 'faster,' denoting time-saving in evidence generation, and 'cheaper,' emphasizing cost-efficiency decision compared to methodologies that do not involve data routinely collected in clinical practice. Metrics and relevant case studies are tailored based on stakeholder value propositions and selected KPIs that can be used to assess what value has been created by using RWE compared to traditional evidence-generation approaches and comparing different RWE sources.
RESULTS: Operationalized through metrics and case studies drawn from the literature, the value of RWE is documented as improving treatment effect heterogeneity evaluation, expanding medical product labels, and expediting post-market compliance. RWE is also shown to reduce the cost and time required to produce evidence compared to traditional one-off approaches. An original example of a metric that measures the time saved by RWE methods to detect a signal of a product failure was presented based on analysis of the National Cardiovascular Disease Registry.
CONCLUSIONS: The framework presented in this manuscript offers a comprehensive approach for evaluating the value of RWE, applicable to all stakeholders engaged in leveraging RWE for healthcare decision-making. Through the proposed metrics and illustrated case studies, valuable insights are provided into the heightened efficiency, cost-effectiveness, and improved decision-making within clinical and regulatory domains facilitated by RWE. While this framework is primarily focused on medical devices, it could potentially inform the determination of RWE value in other medical products. By discerning the variations in cost, time, and data utility among various evidence-generation methods, stakeholders are empowered to invest strategically in RWE infrastructure and shape future research endeavors.

Keywords:  Coordinated Registry Networks (CRN); Cost-efficiency; Healthcare decision-making; Key performance indicators (KPI); Medical devices; Post-market compliance; Real-world evidence (RWE); Stakeholder benefits; Time-saving metrics; Value evaluation framework

DOI:  https://doi.org/10.1007/s43441-024-00680-z
Appl Clin Inform. 2024 Jul 25.

What Do We Mean by Sharing of Patient Data? DaSH - A Data Sharing Hierarchy of Privacy and Ethical Challenges.

Richard Schreiber, Ross Koppel, Bonnie Kaplan.

BACKGROUND: Sharing of clinical data is common and necessary for patient care, research, public health, and innovation. The term "data sharing," however, is often ambiguous in its many facets and complexities-each of which involves ethical, legal, and social issues. To our knowledge there is no extant hierarchy of data sharing that assesses these issues.OBJECTIVE: Develop a hierarchy explicating the risks and ethical complexities of data sharing with particular focus on patient data privacy.
METHODS: We surveyed the available peer-reviewed and gray literature, and with our combined extensive experience in bioethics and medical informatics, created this hierarchy.
RESULTS: We present six ways data are shared and provide a tiered Data Sharing Hierarchy (DaSH) of risks, showing increasing threats to patients' privacy and to clinicians and organizations as one progresses up the hierarchy from data sharing for direct patient care, public health and safety, scientific research, commercial purposes, complex combinations of the preceding efforts, and among networked third parties. We offer recommendations to enhance benefits of data sharing while mitigating risks and protecting patients' interests by: improving consenting; developing better policies and procedures; clarifying, simplifying, and updating regulation to include all health-related data regardless of source; expanding the scope of bioethics for information technology; and increasing ongoing monitoring and research.
CONCLUSIONS: Data sharing, while essential for patient care, is increasingly complex, opaque, and perhaps perilous for patients, clinicians and healthcare institutions. Risks increase with advances in technology and with more encompassing patient data from wearables and artificial intelligence database mining.
CLINICAL SIGNIFICANCE: Data sharing places responsibilities on all parties: patients, clinicians, researchers, educators, risk managers, attorneys, informaticists, bioethicists, institutions, and policy makers.

DOI: https://doi.org/10.1055/a-2373-3291
Nat Metab. 2024 Jul 24.

Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.

Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

DOI: https://doi.org/10.1038/s42255-024-01081-0
Nat Genet. 2024 Jul 22.

Mitochondrial DNA mosaicism in normal human somatic cells.

Jisong An, Chang Hyun Nam, Ryul Kim, Yunah Lee, Hyein Won, Seongyeol Park, Won Hee Lee, Hansol Park, Christopher J Yoon, Yohan An, Jie-Hyun Kim, Jong Kwan Jun, Jeong Mo Bae, Eui-Cheol Shin, Bun Kim, Yong Jun Cha, Hyun Woo Kwon, Ji Won Oh, Jee Yoon Park, Min Jung Kim, Young Seok Ju.

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.

DOI: https://doi.org/10.1038/s41588-024-01838-z