bims-curels Biomed News
on Leigh syndrome
Issue of 2025–03–09
eightteen papers selected by
Cure Mito Foundation
  1. Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.
  2. Leber's hereditary optic neuropathy and multiple sclerosis: overlap between mitochondrial disease and neuroinflammation.
  3. Research progress on paternal mitochondrial inheritance: An overview.
  4. Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.
  5. Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
  6. Engineered mitochondria in diseases: mechanisms, strategies, and applications.
  7. Two tales of therapeutic innovations for Leigh syndrome spectrum.
  8. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with high-frequency oscillations on scalp EEG: A case report.
  9. Bridging the gap: empowering patients as research partners through a structured training program.
  10. ["Mitochondrial medicine" in the light of the fourth national plan for rare diseases (PNMR4): The example of the MITOMICS project].
  11. Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
  12. Management of anesthesia in a child with mitochondrial disease for dental rehabilitation.
  13. NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
  14. Dodging mitochondrial mislocalization.
  15. The Importance of Genetic Diagnosis in Rare Diseases.
  16. Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
  17. Leber's Hereditary Optic Neuropathy with Retinal Hemorrhage.
  18. Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor.
  1. JCI Insight. 2025 Mar 04. pii: e188962. [Epub ahead of print]
    Vitamin A treatment restores vision failures arising from Leber's hereditary optic neuropathy-linked mtDNA mutation.
    Cheng Ai, Huiying Li, Chunyan Wang, Yanchun Ji, Douglas C Wallace, Junbin Qian, Yimin Zhu, Min-Xin Guan.
      Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood and there has been no effective treatment or cure for this disorder. Using a mice model bearing a LHON-linked ND6P25L mutation, we demonstrated that the mutation caused retinal cell-specific deficiencies, especially in retinal ganglion cells (RGC), rods and Müller cells. Single-cell RNA sequencing revealed cell-specific dysregulation of oxidative phosphorylation and visual signaling pathways in the mutant retina. Strikingly, ND6 mutation-induced dysfunctions caused abnormal vitamin A (VA) metabolism essential for visual function. VA supplementation remarkably alleviated retinal deficiencies, including reduced fundus lesion and retinal thickness, and increasing numbers of RGCs, photoreceptors and Müller cell neurites. The restoration of visual functions with VA treatment were further evidenced by correcting dysregulations of phototransduction cascade and neurotransmitter transmission and restoring electrophysiological properties. Interestingly, VA supplementation markedly rescued the abnormal mitochondrial morphologies and functions in the mutant retina. These findings provide new insight into retina-specific pathophysiology of mitochondrial retinopathy arising from vitamin A deficiency and mitochondrial dysfunction induced by mtDNA mutation and step toward for therapeutic intervention for LHON and other mitochondrial retinopathy.
    Keywords:  Genetic diseases; Genetics; Metabolism; Mitochondria; Mouse models; Ophthalmology
    DOI:  https://doi.org/10.1172/jci.insight.188962
  2. Front Neurol. 2025 ;16 1538358
    Leber's hereditary optic neuropathy and multiple sclerosis: overlap between mitochondrial disease and neuroinflammation.
    Golbarg Rahimi, Mackenzie Silverman, Maeve Lucas, Lilia Kazerooni, Mariam M Yousuf, Saba Jafarpour, Jonathan D Santoro.
      Although Multiple sclerosis (MS) and Leber hereditary optic neuropathy (LHON) have distinct pathophysiological mechanisms, they are both neurodegenerative conditions that involve mitochondrial dysfunction. MS is an autoimmune disease that is characterized by demyelination and neuroinflammation; and LHON is a mitochondrial disorder predominantly affecting the optic nerves, resulting in severe vision loss. Recent studies have highlighted the coexistence of these two conditions, particularly in females, suggesting that mitochondrial variants in LHON may predispose individuals to develop MS or affect its progression. Similar to MS, LHON-MS presents with visual impairment, neurological deficits, white matter lesions, and brain atrophy, which further supports a shared underlying pathophysiology. While MS is not inherently a mitochondrial disorder, its neuroinflammatory processes can lead to mitochondrial dysfunction. Reciprocally, mitochondrial impairment may be exacerbated in LHON-MS. Therefore, the role of mitochondrial dysfunction in these diseases is central, with impaired mitochondrial function contributing to cellular damage and neuroinflammation. This review explores the intersections of MS and LHON, emphasizing the need for further research to better understand mitochondrial dysfunction in these disorders.
    Keywords:  Harding’s syndrome; Leber’s hereditary optic neuropathy; mitochondrial dysfunction; multiple sclerosis; neuroimmunology; neuropathology
    DOI:  https://doi.org/10.3389/fneur.2025.1538358
  3. Mitochondrion. 2025 Feb 28. pii: S1567-7249(25)00016-9. [Epub ahead of print]82 102019
    Research progress on paternal mitochondrial inheritance: An overview.
    Wen Hu, Jiting Zhang, Zhaoqi Wu, Yi Wu, Yuhui Hu, Xiaohui Hu, Jinguo Cao.
      Mitochondria are self-replicating organelles with their own DNA. They play a crucial role in biological, cellular and functional processes, such as energy production, metabolism, and signal transduction. Abnormal mitochondrial function can cause various diseases such as diabetes, tumour, Parkinson's disease, hereditary optic neuropathy, and others. Although mitochondrial functions have been extensively and widely explored, studies on mitochondrial inheritance have been limited. Mitochondrial inheritance is traditionally thought to be maternal although small amounts of paternally transmitted mitochondria have been discovered on rare occasions, and the role of paternal mitochondria transmission to offspring has been largely ignored. This review highlights the present knowledge on mitochondrial inheritance, especially the controversy and the difficulties in investigating paternal mitochondrial inheritance. More significantly, we present a comprehensive description of the physiological functions of paternal mitochondria in children and discuss the animal model to explore the mechanism of paternal mitochondrial inheritance. This review may provide a theoretical and experimental basis for improving our understanding of paternal mitochondrial inheritance, and also provide new ideas for treating mitochondrial diseases.
    Keywords:  Drosophila; Mitochondria; Mitochondrial inheritance; Paternal mitochondrial inheritance
    DOI:  https://doi.org/10.1016/j.mito.2025.102019
  4. Mol Genet Metab. 2025 Feb 21. pii: S1096-7192(25)00049-6. [Epub ahead of print]144(4): 109058
    Improving acute care for Primary Mitochondrial Disease: Development of a publicly available clinical care pathway.
    Matthew M Demczko, Rebecca D Ganetzky, Cassandra Tormey, Brandon C Ku, Bridget Blowey, Jane Lavelle, Amy Goldstein.
      Primary mitochondrial diseases (PMD) are an increasingly recognized cause of multi-system organ dysfunction. Children frequently require acute care in an inpatient setting, though many hospitals do not have access to metabolic specialists. We developed a publicly available, evidenced-based clinical pathway utilizing expert consensus guidelines to guide the care of PMD patients during an emergency department visit and/or hospitalization. Utilization of the pathway may help improve triage time, clarify therapeutic options, and help initiate disease-specific screening.
    Keywords:  Acute care; Care pathways; Mitochondrial disease; Rare disease
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109058
  5. Sci Adv. 2025 Mar 07. 11(10): eadr0690
    Origin and cell type specificity of mitochondrial DNA mutations in C9ORF72 ALS-FTLD human brain organoids.
    Yu Nie, Kornélia Szebényi, Lea M D Wenger, András Lakatos, Patrick F Chinnery.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are primarily genetic in ~20% of patients. Mutations in C9ORF72 are the most frequent cause, but it is not understood why there is notable regional pathology. An increased burden of mitochondrial DNA (mtDNA) mutations in ALS-FTLD brains implicates mitochondrial mechanisms; however, it remains unclear how and when these mutations arise. To address this, we generated cerebral organoids derived from human-induced pluripotent stem cells (hiPSCs) of patients with ALS-FTLD harboring the C9ORF72 hexanucleotide repeat expansion alongside CRISPR-corrected isogenic and healthy controls. Here, we show a higher mtDNA single-nucleotide variant (mtSNV) burden in astroglia derived from C9ORF72-mutant organoids, with some de novo mtSNVs likely due to the C9ORF72 repeat and others evading selection to reach higher heteroplasmy levels. Thus, the functional consequences of the regional accumulation of mtSNVs in C9ORF72 ALS-FTLD brains are likely to manifest through astroglial mitochondrial dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adr0690
  6. Signal Transduct Target Ther. 2025 Mar 03. 10(1): 71
    Engineered mitochondria in diseases: mechanisms, strategies, and applications.
    Mingyang Li, Limin Wu, Haibo Si, Yuangang Wu, Yuan Liu, Yi Zeng, Bin Shen.
      Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.
    DOI:  https://doi.org/10.1038/s41392-024-02081-y
  7. J Neurogenet. 2025 Mar 06. 1-3
    Two tales of therapeutic innovations for Leigh syndrome spectrum.
    Wei-Sheng Lin.
      Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.
    Keywords:  Leigh syndrome; hypoxia; mitochondrial encephalopathy; sildenafil
    DOI:  https://doi.org/10.1080/01677063.2025.2473087
  8. Epilepsy Behav Rep. 2025 Mar;29 100754
    Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with high-frequency oscillations on scalp EEG: A case report.
    Keisuke Maeda, Himari Tsuboi, Nami Hosoda, Junichi Fukumoto, Shiho Fujita, Naohiro Ichino, Keisuke Osakabe, Keiko Sugimoto, Gen Furukawa, Naoko Ishihara.
      Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare mitochondrial disease with a prevalence of 16-18 per 100,000 persons. Most patients with MELAS develop epilepsy and require effective control of recurrent attacks. High-frequency oscillations (HFOs) on scalp EEG are transient bursts of EEG activity with frequencies beyond 80 Hz and are a promising biomarker for seizure control in epilepsy. However, reports on scalp HFOs are limited to some epilepsy syndromes. Herein, we report on the appearance of scalp HFOs in a pediatric patient with MELAS. The patient, a 13-year-old boy, presented with a stroke-like episode at age 9 years and was diagnosed with MELAS. The main symptom was visual disturbances, but epilepsia partialis continua (EPC) was also observed. Scalp EEG recordings were made six times: 8 days before the stroke-like episode (day -8 EEG), the day of appearance (day 1 EEG), and 4, 8, 10, and 100 days after the episode. Analysis of scalp HFOs showed that no scalp HFOs were detected in the day -8 EEG, whereas 1.20 scalp HFOs per minute were detected in the day 1 EEG at the appearance of the stroke-like episode with EPC. The scalp HFO detection rate decreased with the loss of EPC, and no scalp HFOs appeared on EEG, although visual disturbances continued to be observed. By contrast, epileptic discharges remained on EEG after EPC disappearance. Scalp HFOs have the potential to be a useful biomarker for reflecting epileptic seizure in patients with MELAS.
    Keywords:  EEG; Epilepsy; High-frequency oscillation; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
    DOI:  https://doi.org/10.1016/j.ebr.2025.100754
  9. Res Involv Engagem. 2025 Mar 05. 11(1): 17
    Bridging the gap: empowering patients as research partners through a structured training program.
    Ashley Redding, Leah Copeland, Dana Murphy, Karen Clemmons-Lloyd, Kimberly Cummings, John Doyle, Sandy Kesavan, VeRonica Mitchell, Deyal Riley, Linda Stechison, Sara Santarossa.
       BACKGROUND: Engaging patients as partners in the research process is a mutually beneficial endeavor. However, patients may need skills training in order to meaningfully contribute to a project. The present paper describes the training program "A Front Row SEAT to Research," which equipped patient partners to independently lead focus groups and interpret their associated data. The focus groups were an aim of a larger project evaluating the face validity of a scale measuring patient engagement in research.
    MAIN BODY: The nine-week training program, created by Patient Engaged Research Center qualitative research experts, empowered patient partners to conduct qualitative research. The structure of the program included asynchronous video lessons, workbook exercises, and live sessions for practice. Topics covered included a comprehensive overview of the scientific process, qualitative research methods, focus group moderation, planning, coding, data interpretation, and dissemination of findings. A hands-on approach to learning, coupled with the collection of continuous feedback, were hallmarks of the program.
    CONCLUSION: The training program emphasized clear expectations, accessibility, and providing resources to build the capacity of patient partners. Trust was established through a dedicated support person, a collaborative group dynamic, and regular engagement, ensuring patient partners felt valued and empowered. This approach allowed patients to meaningfully contribute to the research and develop a sense of shared ownership in the project.
    Keywords:  Focus groups; Patient empowerment; Patient engagement; Patient involvement; Stakeholder participation; Teaching
    DOI:  https://doi.org/10.1186/s40900-025-00685-4
  10. Med Sci (Paris). 2025 Feb;41(2): 173-179
    ["Mitochondrial medicine" in the light of the fourth national plan for rare diseases (PNMR4): The example of the MITOMICS project].
    Clémence Guillermain, Stéphane Tirard, Sylvie Bannwarth, Vincent Procaccio.
      The aim of the MITOMICS project is to establish a clinical database of patients diagnosed with mitochondrial diseases, combined with a « multiomics » integrated approach in order to gain a better understanding of the molecular mechanisms underlying these diseases, and ultimately, to offer better patient care. The MITOMICS project thus contributes to the consolidation of a French "mitochondrial medicine", a notion that deserves to be examined. With the upcoming launch of the fourth national plan for rare diseases, it is an example of the study and management of rare and ultrarare diseases in France. This article traces the emergence of mitochondrial medicine since the early 1960s. It presents its main characteristics (genocentrism, strong techno-dependence), as well as its major technical and theoretical limitations, with a view to developing personalized mitochondrial medicine for the years to come.
    DOI:  https://doi.org/10.1051/medsci/2025016
  11. Nat Commun. 2025 Mar 06. 16(1): 2250
    Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
    Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.
      Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.
    DOI:  https://doi.org/10.1038/s41467-025-57286-8
  12. J Anaesthesiol Clin Pharmacol. 2025 Jan-Mar;41(1):41(1): 204-205
    Management of anesthesia in a child with mitochondrial disease for dental rehabilitation.
    Maharnab Bhuyan, Sunil Rajan, Pallavi Atri, Jerry Paul.
      
    DOI:  https://doi.org/10.4103/joacp.joacp_542_23
  13. Cell Death Discov. 2025 Mar 01. 11(1): 82
    NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
    Yen-Lin Chen, Brian Hon-Yin Chung, Masakazu Mimaki, Shumpei Uchino, Yin-Hsiu Chien, Christopher Chun-Yun Mak, Steven Shinn-Forng Peng, Wei-Chen Wang, Yu-Li Lin, Wuh-Liang Hwu, Shyh-Jye Lee, Ni-Chung Lee.
      Complex I of the mitochondrial electron transfer chain is one of the largest membrane protein assemblies ever discovered. A patient carrying a homozygous NDUFB7 intronic mutation died within two months after birth due to cardiorespiratory defects, preventing further study. Here, we report another patient with compound heterozygous mutations in NDUFB7 who suffers from pons abnormality, lactic acidosis, prematurity, prenatal and postnatal growth deficiency, incomplete closure of the abdominal wall (ventral hernia), and a poorly functioning gastrointestinal tract (pseudo-obstruction). We demonstrated that the patient's skin fibroblasts are deficient in Complex I assembly and reduced supercomplex formation. This report further broadens the spectrum of mitochondrial disorders. The patient has had several surgeries. After receiving treatment with Coenzyme Q10 and vitamin B complex, she has remained stable up to this point. To further explore the functionality of NDUFB7 in vivo, we knocked down Ndufb7 in zebrafish embryos. This resulted in brain ventricle and neuronal defects, elevated lactic acid levels, and reduced oxygen consumption, indicating defective mitochondrial respiration. These phenotypes can be specifically rescued by ectopic expression of ndufb7. More importantly, Mitoquinone mesylate (MitoQ), a common remedy for mitochondrial disorders, can ameliorate these conditions. These results suggest a role for NDUFB7 in mitochondrial activity and the suitability of the zebrafish model for further drug screening and the development of therapeutic strategies for this rare disease.
    DOI:  https://doi.org/10.1038/s41420-025-02369-0
  14. Nat Rev Mol Cell Biol. 2025 Mar 06.
    Dodging mitochondrial mislocalization.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00840-5
  15. Balkan Med J. 2025 Mar 03. 42(2): 92-93
    The Importance of Genetic Diagnosis in Rare Diseases.
    Hakan Gürkan, Nihan Bilge Satkın.
      
    DOI:  https://doi.org/10.4274/balkanmedj.galenos.2025.2025-270125
  16. Immunol Lett. 2025 Mar 06. pii: S0165-2478(25)00024-0. [Epub ahead of print]274 106992
    Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
    Valentina Artusa, Lara De Luca, Mario Clerici, Daria Trabattoni.
      Mitochondria are more than mere energy generators; they are multifaceted organelles that integrate metabolic, signalling, and immune functions, making them indispensable players in maintaining cellular and systemic health. Mitochondrial transfer has recently garnered attention due to its potential role in several physiological and pathological processes. This process involves multiple mechanisms by which mitochondria, along with mitochondrial DNA and other components, are exchanged between cells. In this review, we examine the critical roles of mitochondrial transfer in health and disease, focusing on its impact on immune cell function, the resolution of inflammation, tissue repair, and regeneration. Additionally, we explore its implications in viral infections and cancer progression. We also provide insights into emerging therapeutic applications, emphasizing its potential to address unmet clinical needs.
    Keywords:  Cancer; Immunity; Inflammation; Mitochondrial transfer; Mitotherapy
    DOI:  https://doi.org/10.1016/j.imlet.2025.106992
  17. Neuroophthalmology. 2025 ;49(2): 127-131
    Leber's Hereditary Optic Neuropathy with Retinal Hemorrhage.
    Yasuyuki Takai, Akiko Yamagami, Mayumi Iwasa, Kenji Inoue, Ryoma Yasumoto, Hitoshi Ishikawa, Masato Wakakura.
      Leber's hereditary optic neuropathy (LHON) causes subacute visual loss, and, in the acute phase, the optic disc shows hyperemia, peripapillary telangiectasia, and swelling of the retinal nerve fiber layer (RNFL). Rarely, retinal hemorrhage may be present. In this study, we investigated LHON cases with retinal hemorrhage in the acute phase. Among 82 cases (164 eyes) of LHON who visited the Inoue Eye Hospital, retinal hemorrhage was observed in 5 cases (5 eyes). The age at onset was 36 (27-46) years, with 4 male cases. Mitochondrial DNA analysis revealed the presence of the m.11778G > A variant in four patients and the m.14484T > C variant in one patient. There was no medical history and no excessive smoking or alcohol consumption in any of the cases. In all cases, retinal hemorrhages were observed in the RNFL, accompanying the characteristic optic disc findings of LHON. Fluorescein angiography performed in three cases showed no leakage from the optic disc or blood vessels. While rare, the presence of retinal hemorrhage along the RNFL during the acute phase of LHON should be recognized, as it may warrant consideration of alternative diagnoses.
    Keywords:  Word; leber’s hereditary optic neuropathy; peripapillary telangiectasia; retinal hemorrhage; retinal nerve fiber layer
    DOI:  https://doi.org/10.1080/01658107.2024.2389957
  18. Front Physiol. 2024 ;15 1488248
    Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor.
    Samantha Rothwell, Irvin Ng, Sophia Shalchy-Tabrizi, Pola Kalinowski, Omnia M Taha, Italia Paris, Angelica Baniqued, Lisa Lin, Michelle M Mezei, Anna Lehman, Lisa M Julian, Damon Poburko.
       Introduction: Mitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium and radical signaling and inflammation. Mitochondrial DNA (mtDNA) replication by the POLG-encoded mitochondrial DNA polymerase (POLG) is critical for mitochondrial health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, through reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy or hyperplasia that drives vascular remodeling associated with hypertension.
    Methods: We characterized the effect of over-expressing POLG variants that were previously observed in a cohort of hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, and p.Arg1138Cys) in A7r5 cells.
    Results: AlphaFold modeling of the POLG holoenzyme complexed with DNA predicted changes in the catalytic site in the p.Tyr955Cys and p.Asn1098Ile variants, while p.Arg964Cys and p.Arg1138Cys showed minimal effects. The POLG variants reduced mtDNA copy number, assessed by immunofluorescence and droplet digital PCR, by up to 27% in the order p.Tyr955Cys > p.Arg964Cys > p.Asn1098Ile > p.Arg1138Cys relative to wild-type-transfected cultures. Loss of mtDNA was reduced in cultures grown in low serum and glucose media, but the cell density was increased in the same rank order in both 10% serum and 1% serum. POLG constructs contained a Myc epitope, the counterstaining for which showed that the mtDNA copy number was reduced in both transfected cells and untransfected neighbors. Live-cell imaging of mitochondrial membrane potential with TMRM and radical oxygen species production with MitoSOX showed little effect of the POLG variants. POLG variants had little effect on oxygen consumption, assessed by Seahorse assay. Live-cell imaging growth analyses again showed increased growth in A7r5 cells transfected with p.Tyr955Cys but a decreased growth with p.Arg1138Cys, while p.Tyr955Cys increased growth of HeLa cells. Conditioned media from HeLa cells transfected with POLG variants reduced doubling times in naïve cultures. Pharmacologically, wedelolactone and MitoTEMPOL, but not indomethacin or PD98059, suppressed the mitogenic effects of p.Tyr955Cys and p.Arg964Cys in A7r5 cells.
    Discussion: We conclude that POLG dysfunction induces secretion of a mitogenic signal from A7r5 and HeLa cells even when changes in mtDNA copy number are below the limit of detection. Such mitogenic stimulation could stimulate hypertrophic remodeling that could contribute to drug-resistant hypertension in patient populations with loss-of-function POLG variants.
    Keywords:  A7r5; IncuCyte; POLG; StarDist; hypertension; mitochondrial DNA; rare disease; vascular smooth muscle
    DOI:  https://doi.org/10.3389/fphys.2024.1488248
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