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Parchwani D, Singh R, Patel D. Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance. World J Methodol 2025; 15:102709. [DOI: 10.5662/wjm.v15.i3.102709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 01/21/2025] [Accepted: 02/08/2025] [Indexed: 03/06/2025] Open
Abstract
The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.
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Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Digisha Patel
- Department of Physiology, Shantabaa Medical College and General Hospital Amreli, Amreli 365601, Gujarāt, India
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2
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Halawani MA, Badeeb NO. The crossroads of Leber hereditary optic neuropathy and autosomal dominant optic Atrophy: Clinical profiles of patients with coexisting pathogenic genetic variants. Am J Ophthalmol Case Rep 2025; 38:102346. [PMID: 40417638 PMCID: PMC12099837 DOI: 10.1016/j.ajoc.2025.102346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 04/22/2025] [Accepted: 04/27/2025] [Indexed: 05/27/2025] Open
Abstract
Purpose Leber Hereditary Optic Neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA) are hereditary optic neuropathies characterized by mitochondrial dysfunctions causing destruction to the retinal ganglion cells and their axons, painless bilateral vision loss and symmetrical temporal pallor of the optic nerve. We present six intrafamilial cases with different manifestations of LHON and/or ADOA and their genetic variant profiles. Observations Two brothers and their father had symptomatic bilateral vision loss, two sisters were asymptomatic, and the mother had left eye vision loss due to solar retinopathy; accompanied with headaches. Five of the patients had normal anterior and posterior segment exam aside from the affected optic nerves. The family pedigree showed an unaffected first generation and an affected male in the second generation. In the third generation, an affected male (the father in this family), diagnosed with optic atrophy due to OPA1 c.2383C > T variant, married a woman (the mother) carrying the LHON MT-ND4 m.11778G > A variant. Their offspring were one unaffected daughter, one affected daughter and two affected sons harboring both LHON and ADOA pathogenic variants inherited from their parents. Conclusion and importance Mitochondrial optic neuropathies, which result in loss of retinal ganglion cells, are a substantial cause of visual impairment. Herein, we report two cases of combined LHON- and ADOA-causing pathogenic variants in two brothers, in addition to the genetic and ophthalmologic profile of their parents and two sisters.
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Affiliation(s)
- Mohammed A. Halawani
- Department of Ophthalmology, King Khalid Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Nooran O. Badeeb
- Department of Surgery, Ophthalmology Devision, College of medicine, University of Jeddah, Saudi Arabia
- Department of Ophthalmology, King Fahad Armed Forces Hospital, Ministry of Defense Health Services, Jeddah, Saudi Arabia
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3
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Shi Y, Xie J, Jiang J, Yan X, Chen X, Hong S, Liu J, Xu G, Su H, Chen W, Wang N, Lin X. A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia. Mov Disord 2025; 40:168-173. [PMID: 39468830 DOI: 10.1002/mds.30048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/12/2024] [Accepted: 10/15/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases. OBJECTIVES To identify novel genetic causes of HSP. METHODS Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family. RESULTS We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria. CONCLUSIONS The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Yan Shi
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Junhao Xie
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Junyi Jiang
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xinyu Yan
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xuejiao Chen
- Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Shunyan Hong
- Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
| | - Jiyuan Liu
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Guorong Xu
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Huizhen Su
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Wanjin Chen
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ning Wang
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xiang Lin
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Vallabh NA, Lane B, Simpson D, Fuchs M, Choudhary A, Criddle D, Cheeseman R, Willoughby C. Massively parallel sequencing of mitochondrial genome in primary open angle glaucoma identifies somatically acquired mitochondrial mutations in ocular tissue. Sci Rep 2024; 14:26324. [PMID: 39487142 PMCID: PMC11530638 DOI: 10.1038/s41598-024-72684-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/10/2024] [Indexed: 11/04/2024] Open
Abstract
Glaucoma is a sight threatening neurodegenerative condition of the optic nerve head associated with ageing and marked by the loss of retinal ganglion cells. Mitochondrial dysfunction plays a crucial role in the pathogenesis of neurodegeneration in the most prevalent type of glaucoma: primary open angle glaucoma (POAG). All previous mitochondrial genome sequencing studies in POAG analyzed mitochondrial DNA (mtDNA) isolated from peripheral blood leukocytes and have not evaluated cells derived from ocular tissue, which better represent the glaucomatous disease context. In this study, we evaluated mitochondrial genome variation and heteroplasmy using massively parallel sequencing of mtDNA in a cohort of patients with POAG, and in a subset assess the role of somatic mitochondrial genome mutations in disease pathogenesis using paired samples of peripheral blood leukocytes and ocular tissue (Tenon's ocular fibroblasts). An enrichment of potentially pathogenic nonsynonymous mtDNA variants was identified in Tenon's ocular fibroblasts from participants with POAG. The absence of oxidative DNA damage and predominance of transition variants support the concept that errors in mtDNA replication represent the predominant mutation mechanism in Tenon's ocular fibroblasts from patients with POAG. Pathogenic somatic mitochondrial genome mutations were observed in people with POAG. This supports the role of somatic mitochondrial genome variants in the etiology of glaucoma.
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Affiliation(s)
- Neeru Amrita Vallabh
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L69 3BX, UK.
- St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK.
| | - Brian Lane
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester, M20 4BX, UK
| | - David Simpson
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, UK
| | - Marc Fuchs
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, UK
| | - Anshoo Choudhary
- St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK
| | - David Criddle
- Institute of Systems, Molecular and Integrative Biology, Biosciences Building, University of Liverpool, Liverpool, L69 7BE, UK
| | - Robert Cheeseman
- St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, L7 8XP, UK
| | - Colin Willoughby
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L69 3BX, UK.
- Genomic Medicine, Biomedical Sciences Research Institute, Ulster University, Coleraine, BT52 1SA, UK.
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5
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Landoni JC, Erkul S, Laalo T, Goffart S, Kivelä R, Skube K, Nieminen AI, Wickström SA, Stewart J, Suomalainen A. Overactive mitochondrial DNA replication disrupts perinatal cardiac maturation. Nat Commun 2024; 15:8066. [PMID: 39277581 PMCID: PMC11401880 DOI: 10.1038/s41467-024-52164-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 08/26/2024] [Indexed: 09/17/2024] Open
Abstract
High mitochondrial DNA (mtDNA) amount has been reported to be beneficial for resistance and recovery of metabolic stress, while increased mtDNA synthesis activity can drive aging signs. The intriguing contrast of these two mtDNA boosting outcomes prompted us to jointly elevate mtDNA amount and frequency of replication in mice. We report that high activity of mtDNA synthesis inhibits perinatal metabolic maturation of the heart. The offspring of the asymptomatic parental lines are born healthy but manifest dilated cardiomyopathy and cardiac collapse during the first days of life. The pathogenesis, further enhanced by mtDNA mutagenesis, involves prenatal upregulation of mitochondrial integrated stress response and the ferroptosis-inducer MESH1, leading to cardiac fibrosis and cardiomyocyte death after birth. Our evidence indicates that the tight control of mtDNA replication is critical for early cardiac homeostasis. Importantly, ferroptosis sensitivity is a potential targetable mechanism for infantile-onset cardiomyopathy, a common manifestation of mitochondrial diseases.
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MESH Headings
- Animals
- DNA, Mitochondrial/genetics
- DNA, Mitochondrial/metabolism
- DNA Replication
- Mice
- Myocytes, Cardiac/metabolism
- Female
- Male
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cardiomyopathy, Dilated/pathology
- Ferroptosis/genetics
- Myocardium/metabolism
- Myocardium/pathology
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/genetics
- Mice, Inbred C57BL
- Animals, Newborn
- Humans
- Heart/physiopathology
- Fibrosis
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Affiliation(s)
- Juan C Landoni
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
| | - Semin Erkul
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tuomas Laalo
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Steffi Goffart
- Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
| | - Riikka Kivelä
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Karlo Skube
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Anni I Nieminen
- Metabolomics Unit, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Sara A Wickström
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - James Stewart
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Anu Suomalainen
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- HUS Diagnostic Centre, Helsinki University Hospital, Helsinki, Finland.
- HiLife, University of Helsinki, Helsinki, Finland.
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6
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Pasqualotto BA, Nelson A, Deheshi S, Sheldon CA, Vogl AW, Rintoul GL. Impaired mitochondrial morphological plasticity and failure of mitophagy associated with the G11778A mutation of LHON. Biochem Biophys Res Commun 2024; 721:150119. [PMID: 38768545 DOI: 10.1016/j.bbrc.2024.150119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/07/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Mitochondrial dynamics were examined in human dermal fibroblasts biopsied from a confirmed Leber's Hereditary Optic Neuropathy (LHON) patient with a homoplasmic G11778A mutation of the mitochondrial genome. Expression of the G11778A mutation did not impart any discernible difference in mitochondrial network morphology using widefield fluorescence microscopy. However, at the ultrastructural level, cells expressing this mutation exhibited an impairment of mitochondrial morphological plasticity when forced to utilize oxidative phosphorylation (OXPHOS) by transition to glucose-free, galactose-containing media. LHON fibroblasts also displayed a transient increase in mitophagy upon transition to galactose media. These results provide new insights into the consequences of the G11778A mutation of LHON and the pathological mechanisms underlying this disease.
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Affiliation(s)
- Bryce A Pasqualotto
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Alexa Nelson
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Samineh Deheshi
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Claire A Sheldon
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada
| | - A Wayne Vogl
- Life Sciences Institute and the Department of Cellular & Physiological Sciences, University of British Columbia, Canada
| | - Gordon L Rintoul
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada.
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7
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Lam BL. Leber hereditary optic neuropathy gene therapy. Curr Opin Ophthalmol 2024; 35:244-251. [PMID: 38117686 PMCID: PMC10959684 DOI: 10.1097/icu.0000000000001028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Abstract
PURPOSE OF REVIEW To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON). RECENT FINDINGS Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally. SUMMARY Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops.
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Affiliation(s)
- Byron L Lam
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
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8
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Vallbona-Garcia A, Lindsey PJ, Kamps R, Stassen APM, Nguyen N, van Tienen FHJ, Hamers IHJ, Hardij R, van Gisbergen MW, Benedikter BJ, de Coo IFM, Webers CAB, Gorgels TGMF, Smeets HJM. Mitochondrial DNA D-loop variants correlate with a primary open-angle glaucoma subgroup. FRONTIERS IN OPHTHALMOLOGY 2024; 3:1309836. [PMID: 38983060 PMCID: PMC11182222 DOI: 10.3389/fopht.2023.1309836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 12/29/2023] [Indexed: 07/11/2024]
Abstract
Introduction Primary open-angle glaucoma (POAG) is a characteristic optic neuropathy, caused by degeneration of the optic nerve-forming neurons, the retinal ganglion cells (RGCs). High intraocular pressure (IOP) and aging have been identified as major risk factors; yet the POAG pathophysiology is not fully understood. Since RGCs have high energy requirements, mitochondrial dysfunction may put the survivability of RGCs at risk. We explored in buffy coat DNA whether mtDNA variants and their distribution throughout the mtDNA could be risk factors for POAG. Methods The mtDNA was sequenced from age- and sex-matched study groups, being high tension glaucoma (HTG, n=71), normal tension glaucoma patients (NTG, n=33), ocular hypertensive subjects (OH, n=7), and cataract controls (without glaucoma; n=30), all without remarkable comorbidities. Results No association was found between the number of mtDNA variants in genes encoding proteins, tRNAs, rRNAs, and in non-coding regions in the different study groups. Next, variants that controls shared with the other groups were discarded. A significantly higher number of exclusive variants was observed in the D-loop region for the HTG group (~1.23 variants/subject), in contrast to controls (~0.35 variants/subject). In the D-loop, specifically in the 7S DNA sub-region within the Hypervariable region 1 (HV1), we found that 42% of the HTG and 27% of the NTG subjects presented variants, while this was only 14% for the controls and OH subjects. As we have previously reported a reduction in mtDNA copy number in HTG, we analysed if specific D-loop variants could explain this. While the majority of glaucoma patients with the exclusive D-loop variants m.72T>C, m.16163 A>G, m.16186C>T, m.16298T>C, and m.16390G>A presented a mtDNA copy number below controls median, no significant association between these variants and low copy number was found and their possible negative role in mtDNA replication remains uncertain. Approximately 38% of the HTG patients with reduced copy number did not carry any exclusive D-loop or other mtDNA variants, which indicates that variants in nuclear-encoded mitochondrial genes, environmental factors, or aging might be involved in those cases. Conclusion In conclusion, we found that variants in the D-loop region may be a risk factor in a subgroup of POAG, possibly by affecting mtDNA replication.
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Affiliation(s)
- Antoni Vallbona-Garcia
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Patrick J Lindsey
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Rick Kamps
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Alphons P M Stassen
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
| | - Nhan Nguyen
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Florence H J van Tienen
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Ilse H J Hamers
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Rianne Hardij
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Marike W van Gisbergen
- Department of Dermatology, Maastricht University Medical Center, Maastricht, Netherlands
- GROW School for Oncology and Reproduction, Maastricht University, Maastricht, Netherlands
| | - Birke J Benedikter
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Irenaeus F M de Coo
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Carroll A B Webers
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Theo G M F Gorgels
- University Eye Clinic Maastricht, Maastricht University Medical Center, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Hubert J M Smeets
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
- School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
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9
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Schrott S, Osman C. Two mitochondrial HMG-box proteins, Cim1 and Abf2, antagonistically regulate mtDNA copy number in Saccharomyces cerevisiae. Nucleic Acids Res 2023; 51:11813-11835. [PMID: 37850632 PMCID: PMC10681731 DOI: 10.1093/nar/gkad849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/21/2023] [Accepted: 09/24/2023] [Indexed: 10/19/2023] Open
Abstract
The mitochondrial genome, mtDNA, is present in multiple copies in cells and encodes essential subunits of oxidative phosphorylation complexes. mtDNA levels have to change in response to metabolic demands and copy number alterations are implicated in various diseases. The mitochondrial HMG-box proteins Abf2 in yeast and TFAM in mammals are critical for mtDNA maintenance and packaging and have been linked to mtDNA copy number control. Here, we discover the previously unrecognized mitochondrial HMG-box protein Cim1 (copy number influence on mtDNA) in Saccharomyces cerevisiae, which exhibits metabolic state dependent mtDNA association. Surprisingly, in contrast to Abf2's supportive role in mtDNA maintenance, Cim1 negatively regulates mtDNA copy number. Cells lacking Cim1 display increased mtDNA levels and enhanced mitochondrial function, while Cim1 overexpression results in mtDNA loss. Intriguingly, Cim1 deletion alleviates mtDNA maintenance defects associated with loss of Abf2, while defects caused by Cim1 overexpression are mitigated by simultaneous overexpression of Abf2. Moreover, we find that the conserved LON protease Pim1 is essential to maintain low Cim1 levels, thereby preventing its accumulation and concomitant repressive effects on mtDNA. We propose a model in which the protein ratio of antagonistically acting Cim1 and Abf2 determines mtDNA copy number.
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Affiliation(s)
- Simon Schrott
- Faculty of Biology, Ludwig-Maximilians-Universität München, Großhaderner Str. 2, Planegg-Martinsried 82152, Germany
| | - Christof Osman
- Faculty of Biology, Ludwig-Maximilians-Universität München, Großhaderner Str. 2, Planegg-Martinsried 82152, Germany
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10
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Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J. Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy. Cells 2023; 12:2013. [PMID: 37566092 PMCID: PMC10416882 DOI: 10.3390/cells12152013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.
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Affiliation(s)
- Hoda Shamsnajafabadi
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
| | - Robert E. MacLaren
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
- Oxford Eye Hospital, Oxford University NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Jasmina Cehajic-Kapetanovic
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
- Oxford Eye Hospital, Oxford University NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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11
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Picca A, Guerra F, Calvani R, Coelho-Júnior HJ, Leeuwenburgh C, Bucci C, Marzetti E. The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration. Exp Gerontol 2023; 178:112203. [PMID: 37172915 DOI: 10.1016/j.exger.2023.112203] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/24/2023] [Accepted: 05/09/2023] [Indexed: 05/15/2023]
Abstract
Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.
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Affiliation(s)
- Anna Picca
- Department of Medicine and Surgery, LUM University, 70100 Casamassima, Italy; Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy
| | - Flora Guerra
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy; Department of Geriatrics and Orthopedics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
| | - Hélio José Coelho-Júnior
- Department of Geriatrics and Orthopedics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | | | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
| | - Emanuele Marzetti
- Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, 00168 Rome, Italy; Department of Geriatrics and Orthopedics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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12
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Vallbona-Garcia A, Hamers IHJ, van Tienen FHJ, Ochoteco-Asensio J, Berendschot TTJM, de Coo IFM, Benedikter BJ, Webers CAB, Smeets HJM, Gorgels TGMF. Low mitochondrial DNA copy number in buffy coat DNA of primary open-angle glaucoma patients. Exp Eye Res 2023; 232:109500. [PMID: 37178956 DOI: 10.1016/j.exer.2023.109500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/22/2023] [Accepted: 05/09/2023] [Indexed: 05/15/2023]
Abstract
Primary open-angle glaucoma (POAG) is characterized by optic nerve degeneration and irreversible loss of retinal ganglion cells (RGCs). The pathophysiology is not fully understood. Since RGCs have a high energy demand, suboptimal mitochondrial function may put the survival of these neurons at risk. In the present study, we explored whether mtDNA copy number or mtDNA deletions could reveal a mitochondrial component in POAG pathophysiology. Buffy coat DNA was isolated from EDTA blood of age- and sex-matched study groups, namely POAG patients with high intraocular pressure (IOP) at diagnosis (high tension glaucoma: HTG; n = 97), normal tension glaucoma patients (NTG, n = 37), ocular hypertensive controls (n = 9), and cataract controls (without glaucoma; n = 32), all without remarkable comorbidities. The number of mtDNA copies was assessed through qPCR quantification of the mitochondrial D-loop and nuclear B2M gene. Presence of the common 4977 base pair mtDNA deletion was assessed by a highly sensitive breakpoint PCR. Analysis showed that HTG patients had a lower number of mtDNA copies per nuclear DNA than NTG patients (p-value <0.01, Dunn test) and controls (p-value <0.001, Dunn test). The common 4977 base pair mtDNA deletion was not detected in any of the participants. A lower mtDNA copy number in blood of HTG patients suggests a role for a genetically defined, deficient mtDNA replication in the pathology of HTG. This may cause a low number of mtDNA copies in RGCs, which together with aging and high IOP, may lead to mitochondrial dysfunction, and contribute to glaucoma pathology.
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Affiliation(s)
- Antoni Vallbona-Garcia
- University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
| | - Ilse H J Hamers
- Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands
| | - Florence H J van Tienen
- Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | | | - Tos T J M Berendschot
- University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Irenaeus F M de Coo
- Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands
| | - Birke J Benedikter
- University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Carroll A B Webers
- University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Hubert J M Smeets
- Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
| | - Theo G M F Gorgels
- University Eye Clinic Maastricht, Maastricht University Medical Center+, Maastricht, the Netherlands; School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands
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13
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Holt AG, Davies AM. A comparison of mtDNA deletion mutant proliferation mechanisms. J Theor Biol 2022; 551-552:111244. [PMID: 35973607 DOI: 10.1016/j.jtbi.2022.111244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/17/2022] [Accepted: 08/08/2022] [Indexed: 11/18/2022]
Abstract
In this paper we use simulation methods to investigate the proliferation of deletion mutations of mitochondrial DNA in neurons. We simulate three mtDNA proliferation mechanisms, namely, random drift, replicative advantage and vicious cycle. For each mechanism, we investigated the effect mutation rates have on neuron loss within a human host. We also compare heteroplasmy of each mechanism at mutation rates that yield the levels neuron loss that would be associated with dementia. Both random drift and vicious cycle predicted high levels of heteroplasmy, while replicative advantage showed a small number of dominant clones with a low background of heteroplasmy.
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14
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Andreeva NA, Murakhovskaya YK, Tsygankova PG, Krilova TD, Sheremet NL. [Leber's hereditary optic neuropathy clinical features in patients with mitochondrial DNA m.13513G>A candidate mutation]. Vestn Oftalmol 2022; 138:208-214. [PMID: 36287157 DOI: 10.17116/oftalma2022138052208] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
UNLABELLED Leber's hereditary optic neuropathy (LHON) is caused by primary mtDNA by both primary mtDNA mutations and new mtDNA mutations. The last ones, when detected in several independent LHON families, receive candidate status. The description of new LHON-associated mtDNA mutation is relevant. PURPOSE To determine the LHON clinical features in patients with the m.13513G>A mutation and to estimate the patients' proportion with this pathogenic variant in the LHON patients' sample. MATERIAL AND METHODS The study included 5 LHON patients, associated with m.13513G>A mutation in the ND5 gene in the heteroplasmic state. A standard examination was performed, including color blindness test, visual fields test, spectral optical coherence tomography. RESULTS LHON, associated with m.13513G>A in the heteroplasmic state in the range of 25-60%, is characterized by visual impairment without additional neurological or other extraocular symptoms. Visual recovery to 0.3-1.0 presents in all patients; the visual recovery onset occurs between 12 and 20 months from the disease manifestation. The decrease of the central scotoma size and its density and the color vision improvement are also observed as well as the average retinal nerve fibers layer and ganglion cell complex thickness decrease. The m.13513G>A mutation frequency is 5% in 100 LHON patients' sample and 22.5% in 22 LHON patients with rare and candidate mtDNA mutations. CONCLUSION The m.13513G>A mutation can be considered as primary LHON mutation. The list of pathogenic variants recommended for testing LHON can include this mutation. The m.13513 G>A mutation determines the mild LHON course and good visual functions prognosis in these patients.
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Affiliation(s)
- N A Andreeva
- Research Institute of Eye Diseases, Moscow, Russia
| | | | - P G Tsygankova
- N.P. Bochkov Research Centre for Medical Genetics, Moscow, Russia
| | - T D Krilova
- N.P. Bochkov Research Centre for Medical Genetics, Moscow, Russia
| | - N L Sheremet
- Research Institute of Eye Diseases, Moscow, Russia
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15
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Blood biomarkers for assessment of mitochondrial dysfunction: An expert review. Mitochondrion 2021; 62:187-204. [PMID: 34740866 DOI: 10.1016/j.mito.2021.10.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/28/2021] [Accepted: 10/28/2021] [Indexed: 12/20/2022]
Abstract
Although mitochondrial dysfunction is the known cause of primary mitochondrial disease, mitochondrial dysfunction is often difficult to measure and prove, especially when biopsies of affected tissue are not available. In order to identify blood biomarkers of mitochondrial dysfunction, we reviewed studies that measured blood biomarkers in genetically, clinically or biochemically confirmed primary mitochondrial disease patients. In this way, we were certain that there was an underlying mitochondrial dysfunction which could validate the biomarker. We found biomarkers of three classes: 1) functional markers measured in blood cells, 2) biochemical markers of serum/plasma and 3) DNA markers. While none of the reviewed single biomarkers may perfectly reveal all underlying mitochondrial dysfunction, combining biomarkers that cover different aspects of mitochondrial impairment probably is a good strategy. This biomarker panel may assist in the diagnosis of primary mitochondrial disease patients. As mitochondrial dysfunction may also play a significant role in the pathophysiology of multifactorial disorders such as Alzheimer's disease and glaucoma, the panel may serve to assess mitochondrial dysfunction in complex multifactorial diseases as well and enable selection of patients who could benefit from therapies targeting mitochondria.
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16
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Meunier I, Bocquet B, Defoort-Dhellemmes S, Smirnov V, Arndt C, Picot MC, Dollfus H, Charif M, Audo I, Huguet H, Zanlonghi X, Lenaers G. Characterization of SSBP1-related optic atrophy and foveopathy. Sci Rep 2021; 11:18703. [PMID: 34548540 PMCID: PMC8455542 DOI: 10.1038/s41598-021-98150-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 09/03/2021] [Indexed: 11/17/2022] Open
Abstract
Dominant optic atrophy (DOA) is genetically heterogeneous and most commonly caused by mutations in OPA1. To distinguish between the classical OPA1-related and the recently identified SSBP1-related DOAs, the retina and fovea of 27 patients carrying the SSBP1 p.Arg38Gln variant were scrutinized using 20° × 20° macular cube and 30° and 55° field fundus autofluorescence photographs. Age of onset, visual acuity, retinal nerve fiber layer and macular thicknesses were recorded. Three SSBP1-patients were asymptomatic, 10 had isolated DOA, and 12 had a combined DOA plus foveopathy. The foveopathy, with a tiny defect of the ellipsoid and interdigitation lines, was similar in all patients, independent of age. There were no significant statistical differences in terms of visual acuity and SD-OCT measurements between patients with isolated DOA (mean visual acuity in decimals: 0.54 ± 0.41) and those with combined foveopathy (0.50 ± 0.23). Two patients over 50 years of age developed a progressive rod-cone dystrophy, leading to severe visual impairment. SSBP1-related DOA shares similarities with OPA1-related DOA with an incomplete penetrance and an early childhood visual impairment. Nevertheless, the presence of a congenital foveopathy with no impact on visual acuity is a major criterion to distinguish SSBP1 cases and orient the appropriate genetic analysis.
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Affiliation(s)
- Isabelle Meunier
- National reference centre for inherited sensory diseases, University Hospital of Montpellier, University of Montpellier, Montpellier, France. .,Sensgene Care Network, Strasbourg, France. .,Institute for Neurosciences of Montpellier, Inserm, University of Montpellier, Montpellier, France.
| | - Béatrice Bocquet
- National reference centre for inherited sensory diseases, University Hospital of Montpellier, University of Montpellier, Montpellier, France.,Sensgene Care Network, Strasbourg, France.,Institute for Neurosciences of Montpellier, Inserm, University of Montpellier, Montpellier, France
| | - Sabine Defoort-Dhellemmes
- Sensgene Care Network, Strasbourg, France.,Department of Neuro-Ophthalmology and Electrophysiology, Robert Salengro Hospital, Lille, France
| | - Vasily Smirnov
- Sensgene Care Network, Strasbourg, France.,Department of Neuro-Ophthalmology and Electrophysiology, Robert Salengro Hospital, Lille, France
| | - Carl Arndt
- Department of Ophthalmology, University Hospital of Reims, Reims, France
| | - Marie Christine Picot
- Clinical Investigation Center (CIC) and Clinical Research and Epidemiology Unit (URCE), Montpellier, France
| | - Hélène Dollfus
- Sensgene Care Network, Strasbourg, France.,Department of Ophthalmology, National Center for Rare Disorders in Ophthalmic Genetics CARGO, Strasbourg Hospital, Strasbourg, France
| | - Majida Charif
- Genetics and Immuno-Cell Therapy Team, Mohammed First University, Oujda, Morocco
| | - Isabelle Audo
- Sensgene Care Network, Strasbourg, France.,CNRS, INSERM, Institut de la Vision, Sorbonne Université, Paris, France.,DHU Sight Restore, INSERM-DHOS CIC1423, CHNO des Quinze-Vingts, Paris, France
| | - Hélèna Huguet
- Clinical Investigation Center (CIC) and Clinical Research and Epidemiology Unit (URCE), Montpellier, France
| | - Xavier Zanlonghi
- Sensgene Care Network, Strasbourg, France.,Clinic Jules Verne, Nantes, France.,Department of Ophthalmology, University Hospital of Rennes, Rennes, France
| | - Guy Lenaers
- UMR CNRS 6015 - INSERM U1083, University of Angers MitoLab Team, University Hospital of Angers, Angers, France
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17
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Zanfardino P, Doccini S, Santorelli FM, Petruzzella V. Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain. Int J Mol Sci 2021; 22:8325. [PMID: 34361091 PMCID: PMC8348117 DOI: 10.3390/ijms22158325] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.
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Affiliation(s)
- Paola Zanfardino
- Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Stefano Doccini
- IRCCS Fondazione Stella Maris, Calambrone, 56128 Pisa, Italy;
| | | | - Vittoria Petruzzella
- Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70124 Bari, Italy;
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18
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Li J, Tran OT, Crowley TB, Moore TM, Zackai EH, Emanuel BS, McDonald-McGinn DM, Gur RE, Wallace DC, Anderson SA. Association of Mitochondrial Biogenesis With Variable Penetrance of Schizophrenia. JAMA Psychiatry 2021; 78:911-921. [PMID: 34009292 PMCID: PMC8135063 DOI: 10.1001/jamapsychiatry.2021.0762] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
IMPORTANCE Discovery of mechanisms that underlie variable penetrance for neuropsychiatric illness in the context of genetic variants that carry elevated risk can advance novel treatment approaches for these disorders. OBJECTIVE To test the hypothesis that mitochondrial compensation is associated with the variable penetrance of schizophrenia in the 22q11.2 deletion syndrome (22q11DS). DESIGN, SETTING, AND PARTICIPANTS This case-control study compared measures of mitochondrial function and the expression of related genes in 14 induced pluripotent stem cell-derived neurons from typically developing control individuals (6 lines) and from adults with 22q11DS (8 lines). The individuals with 22q11DS included 2 groups, those carrying a diagnosis of schizophrenia and those without this diagnosis (4 lines each). Similar measures were made of lymphoblastic cells lines (LCLs) from a separate group of adults with 22q11DS with (10 lines) or without (8 lines) schizophrenia. The study included samples derived from a clinical setting. The induced pluripotent stem cell lines were derived from individuals with 22q11DS with or without a diagnosis of schizophrenia at Stanford University. The LCLs were from adults within the 22q and You Center at the Children's Hospital of Philadelphia. Data were analyzed between July 1, 2019, and January 24, 2021. MAIN OUTCOMES AND MEASURES Total adenosine triphosphate (ATP), oxidative phosphorylation (OXPHOS) complex activity, and messenger RNA expression via reverse transcription-polymerase chain reaction of selected genes encoding for mitochondrial proteins. RESULTS Study participants included men and women aged 18 to 37 years. Of 32 participants, the mean (SD) age of men was 27 (1.9) years and of women was 29 (1.2) years. Replicating a previous study, neurons from the 22q11DS and schizophrenia (22q+Sz) group had reduced ATP levels (mean [SD], 15.6 [1.5] vs 21.9 [1.4]; P = .02) and reduced OXPHOS activity (ie, complex I; 1.51 [0.1] vs 1.89 [0.1]; P = .01). These deficits were not present in neurons from individuals with 22q11DS without schizophrenia (22q[-]Sz). In this group, the expression of multiple genes encoding OXPHOS subunits was significantly upregulated. For example, compared with control individuals, NDUFV2 expression was increased by 50% in the 22q(-)Sz group (P < .001) but not significantly changed in the 22q+Sz group. Expression of genes driving mitochondrial biogenesis, including PGC1α, showed a similar pattern of upregulation in the 22q(-)Sz group compared with the control and the 22q+Sz groups. Stimulation of mitochondrial biogenesis normalizes the ATP deficit seen in 22q+Sz neurons. Finally, using LCLs from a separate group of adults with 22q11DS, evidence for enhanced mitochondrial biogenesis was again found in the 22q(-)Sz group. CONCLUSIONS AND RELEVANCE In this study, an increase in mitochondrial biogenesis and function was associated with the absence of schizophrenia in neurons and LCLs from individuals with 22q11DS, but the deficit in the 22q+Sz group was reversible by agents that enhance mitochondrial biogenesis. Enhancement of mitochondrial biogenesis may provide a targetable opportunity for treatment or prevention of this disorder in individuals with 22q11DS.
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Affiliation(s)
- Jianping Li
- Department of Child and Adolescent Psychiatry and Behavioral Sciences, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Oanh T. Tran
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - T. Blaine Crowley
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Tyler M. Moore
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Elaine H. Zackai
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Beverly S. Emanuel
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Donna M. McDonald-McGinn
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Raquel E. Gur
- Department of Child and Adolescent Psychiatry and Behavioral Sciences, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Douglas C. Wallace
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia,Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia
| | - Stewart A. Anderson
- Department of Child and Adolescent Psychiatry and Behavioral Sciences, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania,Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
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19
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Ng WSV, Trigano M, Freeman T, Varrichio C, Kandaswamy DK, Newland B, Brancale A, Rozanowska M, Votruba M. New avenues for therapy in mitochondrial optic neuropathies. THERAPEUTIC ADVANCES IN RARE DISEASE 2021; 2:26330040211029037. [PMID: 37181108 PMCID: PMC10032437 DOI: 10.1177/26330040211029037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 05/16/2023]
Abstract
Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed. Plain language summary Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.
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Affiliation(s)
| | - Matthieu Trigano
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Thomas Freeman
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Carmine Varrichio
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Dinesh Kumar Kandaswamy
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Ben Newland
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Andrea Brancale
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Malgorzata Rozanowska
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Marcela Votruba
- School of Optometry and Vision Sciences,
Cardiff University, Maindy Road, Cardiff, CF24 4HQ, Wales, UK; Cardiff Eye
Unit, University Hospital of Wales, Cardiff, UK
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20
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Filograna R, Mennuni M, Alsina D, Larsson NG. Mitochondrial DNA copy number in human disease: the more the better? FEBS Lett 2020; 595:976-1002. [PMID: 33314045 PMCID: PMC8247411 DOI: 10.1002/1873-3468.14021] [Citation(s) in RCA: 265] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/02/2020] [Accepted: 11/26/2020] [Indexed: 12/19/2022]
Abstract
Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.
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Affiliation(s)
- Roberta Filograna
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - Mara Mennuni
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - David Alsina
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
| | - Nils-Göran Larsson
- Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.,Max Planck Institute for Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, Sweden
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21
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Jiang P, Zhang S, Cheng C, Gao S, Tang M, Lu L, Yang G, Chai R. The Roles of Exosomes in Visual and Auditory Systems. Front Bioeng Biotechnol 2020; 8:525. [PMID: 32582658 PMCID: PMC7283584 DOI: 10.3389/fbioe.2020.00525] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/04/2020] [Indexed: 12/16/2022] Open
Abstract
Exosomes are nanoscale membrane-enclosed vesicles 30-150 nm in diameter that are originated from a number of type cells by the endocytic pathway and consist of proteins, lipids, RNA, and DNA. Although, exosomes were initially considered to be cellular waste, they have gradually been recognized to join in cell-cell communication and cell signal transmission. In addition, exosomal contents can be applied as biomarkers for clinical judgment and exosomes can as potential carriers in a novel drug delivery system. Unfortunately, purification methods of exosomes remain an obstacle. We described some common purification methods and highlight Morpho Menelaus (M. Menelaus) butterfly wings can be developed as efficient methods for exosome isolation. Furthermore, the current research on exosomes mainly focused on their roles in cancer, while related studies on exosomes in the visual and auditory systems are limited. Here we reviewed the biogenesis and contents of exosomes. And more importantly, we summarized the roles of exosomes and provided prospective for exosome research in the visual and auditory systems.
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Affiliation(s)
- Pei Jiang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Shasha Zhang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China
| | - Cheng Cheng
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, China.,Research Institute of Otolaryngology, Nanjing, China
| | - Song Gao
- Department of Otolaryngology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China
| | - Mingliang Tang
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Cardiovascular Science, Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, China
| | - Ling Lu
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, China
| | - Guang Yang
- Department of Otorhinolaryngology, Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, Shanghai, China
| | - Renjie Chai
- MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Science and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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22
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Bahr T, Welburn K, Donnelly J, Bai Y. Emerging model systems and treatment approaches for Leber's hereditary optic neuropathy: Challenges and opportunities. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165743. [PMID: 32105823 PMCID: PMC9252426 DOI: 10.1016/j.bbadis.2020.165743] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/17/2020] [Accepted: 02/21/2020] [Indexed: 12/24/2022]
Abstract
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease mainly affecting retinal ganglion cells (RGCs). The pathogenesis of LHON remains ill-characterized due to a historic lack of effective disease models. Promising models have recently begun to emerge; however, less effective models remain popular. Many such models represent LHON using non-neuronal cells or assume that mutant mtDNA alone is sufficient to model the disease. This is problematic because context-specific factors play a significant role in LHON pathogenesis, as the mtDNA mutation itself is necessary but not sufficient to cause LHON. Effective models of LHON should be capable of demonstrating processes that distinguish healthy carrier cells from diseased cells. In light of these considerations, we review the pathophysiology of LHON as it relates to old, new and future models. We further discuss treatments for LHON and unanswered questions that might be explored using these new model systems.
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Affiliation(s)
- Tyler Bahr
- University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio, Texas 78229. First Author
| | - Kyle Welburn
- University of the Incarnate Word School of Medicine 7615 Kennedy Hill Drive, San Antonio, Texas 78235 Contributing Author
| | - Jonathan Donnelly
- University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio, Texas 78229. Contributing author
| | - Yidong Bai
- University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio, Texas 78229
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23
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Shim HB, Arshad O, Gadawska I, Côté HCF, Hsieh AYY. Platelet mtDNA content and leukocyte count influence whole blood mtDNA content. Mitochondrion 2020; 52:108-114. [PMID: 32156645 DOI: 10.1016/j.mito.2020.03.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023]
Abstract
Changes in whole blood (WB) mitochondrial DNA (mtDNA) content are associated with health and disease. Platelet-derived mtDNA can confound WB mtDNA content measurements. From a sample of 44 volunteers, we show that platelet mtDNA content and platelet:leukocyte ratio are both dependent predictors of WB mtDNA content, but that platelet count itself is not. Furthermore, when platelet:leukocyte ratio increased by <2-fold ex vivo, the effect on WB mtDNA content was minimal. Altogether, this study clarifies the contribution of platelet mtDNA content rather than platelet count on WB mtDNA content measurements, and identifies defined parameters for future research on WB mtDNA content.
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Affiliation(s)
- Hanjoo B Shim
- Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall #4302, Vancouver, British Columbia, Canada
| | - Omair Arshad
- Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall #4302, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Izabella Gadawska
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Hélène C F Côté
- Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall #4302, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Women's Health Research Institute, Vancouver, British Columbia, Canada.
| | - Anthony Y Y Hsieh
- Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall #4302, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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24
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Sheremet NL, Andreeva NA, Shmel'kova MS, Tsigankova PG. [Mitochondrial biogenesis in hereditary optic neuropathies]. Vestn Oftalmol 2019; 135:85-91. [PMID: 31714518 DOI: 10.17116/oftalma201913505185] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The article offers a review of mitochondrial biogenesis in hereditary optic neuropathies. It covers the mechanisms of mitochondrial biogenesis, factors affecting it and tools for mitochondrial turnover assessment.
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Affiliation(s)
- N L Sheremet
- Research Institute of Eye Diseases, 11A Rossolimo St., Moscow, Russian Federation, 119021
| | - N A Andreeva
- Research Institute of Eye Diseases, 11A Rossolimo St., Moscow, Russian Federation, 119021
| | - M S Shmel'kova
- Research Institute of Eye Diseases, 11A Rossolimo St., Moscow, Russian Federation, 119021
| | - P G Tsigankova
- Research Centre for Medical Genetics, 1 Moskvorech'e St., Moscow, Russian Federation, 115522
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25
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Abstract
PURPOSE OF REVIEW Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need. RECENT FINDINGS There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder.
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26
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Li S, Duan S, Qin Y, Lin S, Zheng K, Li X, Zhang L, Gu X, Yao K, Wang B. Leber's Hereditary Optic Neuropathy-Specific Heteroplasmic Mutation m.14495A>G Found in a Chinese Family. Transl Vis Sci Technol 2019; 8:3. [PMID: 31316863 PMCID: PMC6615366 DOI: 10.1167/tvst.8.4.3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 05/06/2019] [Indexed: 01/25/2023] Open
Abstract
Purpose Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA)-associated, maternally inherited eye disease. Mutation heteroplasmy level is one of the leading causes to trigger LHON manifestation. In this study, we aimed to identify the causative mutation in a large Han Chinese family with LHON and explore the underlying pathogenic mechanism in this LHON family. Methods The whole-mtDNA sequence was amplified by long-range PCR. Mutations were subsequently identified by next-generation sequencing (NGS) and validated by Sanger sequencing. The heteroplasmy rates of those family members were determined by digital PCR (dPCR). Mitochondrial haplogroups were assigned based on mtDNA tree build 17. Results The m.14495A>G mutation was identified as causative due to its higher heteroplasmy level (>50%) in patients than in their unaffected relatives. All mutation carriers belong to M7b1a1 and are assigned to Asian mtDNA lineage. Interestingly, our result revealed that high mtDNA copy number in carrier might prevent LHON manifestation. Conclusions This is the first report of m.14495A>G mutation in Asian individuals with LHON. Our study shows that dPCR technology can provide more reliable results in mutation heteroplasmy assay and determination of the cellular mtDNA content, making it a potentially promising tool for clinical precise diagnosis of LHON. Furthermore, our results also add evidence to the opinion that higher mtDNA content may protect mutation carriers from LHON. Translational Relevance dPCR can be used for the assessment of LHON disease, and a new genetic-based diagnostic strategy has been proposed for LHON patients with the m.14495A>G mutation.
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Affiliation(s)
- Shouqing Li
- Department of Neuro-ophthalmology, Weifang Eye Hospital, Shandong Province, China
| | - Shan Duan
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
| | - Yueyuan Qin
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
| | - Sheng Lin
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
| | - Kaifeng Zheng
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
| | - Xi Li
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
| | - Linghua Zhang
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China
| | - Xueying Gu
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China
| | - Keqin Yao
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China
| | - Baojiang Wang
- Laboratory of Medical Genetics, Shenzhen Health Development Research Center, Shenzhen, China.,Center for Birth Defect Research and Prevention, Shenzhen Health Development Research Center, Shenzhen, China
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27
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Bianco A, Valletti A, Longo G, Bisceglia L, Montoya J, Emperador S, Guerriero S, Petruzzella V. Mitochondrial DNA copy number in affected and unaffected LHON mutation carriers. BMC Res Notes 2018; 11:911. [PMID: 30572950 PMCID: PMC6302380 DOI: 10.1186/s13104-018-4025-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/17/2018] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVES Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON penetrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations. DATA DESCRIPTION We collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.
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Affiliation(s)
- Angelica Bianco
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso - Università degli Studi Aldo Moro, Piazza G. Cesare, 70124 Bari, Italy
| | - Alessio Valletti
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso - Università degli Studi Aldo Moro, Piazza G. Cesare, 70124 Bari, Italy
| | - Giovanna Longo
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso - Università degli Studi Aldo Moro, Piazza G. Cesare, 70124 Bari, Italy
| | - Luigi Bisceglia
- Ospedale Casa Sollievo della Sofferenza IRCCS, UOC Genetica Medica, San Giovanni Rotondo, Italy
| | - Julio Montoya
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50013 Zaragoza, Spain
| | - Sonia Emperador
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza-CIBER de Enfermedades Raras (CIBERER)-Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50013 Zaragoza, Spain
| | - Silvana Guerriero
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso - Università degli Studi Aldo Moro, Piazza G. Cesare, 70124 Bari, Italy
| | - Vittoria Petruzzella
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso - Università degli Studi Aldo Moro, Piazza G. Cesare, 70124 Bari, Italy
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28
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Bioactivity and gene expression profiles of hiPSC-generated retinal ganglion cells in MT-ND4 mutated Leber's hereditary optic neuropathy. Exp Cell Res 2018; 363:299-309. [PMID: 29366807 DOI: 10.1016/j.yexcr.2018.01.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 01/09/2018] [Accepted: 01/15/2018] [Indexed: 01/01/2023]
Abstract
Leber's hereditary optic neuropathy (LHON) is the maternally inherited mitochondrial disease caused by homoplasmic mutations in mitochondrial electron transport chain Complex I subunit genes. The mechanism of its incomplete penetrance is still largely unclear. In this study, we created the patient-specific human induced pluripotent stem cells (hiPSCs) from MT-ND4 mutated LHON-affected patient, asymptomatic mutation carrier and healthy control, and differentiated them into retinal ganglion cells (RGCs). We found the defective neurite outgrowth in affected RGCs, but not in the carrier RGCs which had significant expression of SNCG gene. We observed enhanced mitochondrial biogenesis in affected and carrier derived RGCs. Surprisingly, we observed increased NADH dehydrogenase enzymatic activity of Complex I in hiPSC-derived RGCs of asymptomatic carrier, but not of the affected patient. LHON mutation substantially decreased basal respiration in both affected and unaffected carrier hiPSCs, and had the same effect on spare respiratory capacity, which ensures normal function of mitochondria in conditions of increased energy demand or environmental stress. The expression of antioxidant enzyme catalase was decreased in affected and carrier patient hiPSC-derived RGCs as compared to the healthy control, which might indicate to higher oxidative stress-enriched environment in the LHON-specific RGCs. Microarray profiling demonstrated enhanced expression of cell cycle machinery and downregulation of neuronal specific genes.
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29
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Inoue-Yanagimachi M, Himori N, Sato K, Kokubun T, Asano T, Shiga Y, Tsuda S, Kunikata H, Nakazawa T. Association between mitochondrial DNA damage and ocular blood flow in patients with glaucoma. Br J Ophthalmol 2018; 103:1060-1065. [DOI: 10.1136/bjophthalmol-2018-312356] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/24/2018] [Accepted: 08/13/2018] [Indexed: 02/03/2023]
Abstract
Background/AimsWe determined the relationship between tissue mean blur rate (MT) and mitochondrial dysfunction, represented by the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio. We also investigated the usefulness of these biomarkers.MethodsWe assessed ocular blood flow in 123 eyes of 123 patients with open-angle glaucoma (OAG) and 37 control eyes of 37 healthy subjects by measuring MT in the optic nerve head with laser speckle flowgraphy. We measured mtDNA and nDNA with PCR, calculated the mtDNA/nDNA ratio and compared this ratio with MT using Spearman’s rank test. We used multiple regression analysis to further investigate the association between MT and glaucoma in the most severe group.ResultsThe control and the patients with glaucoma had significant differences in the mtDNA/nDNA ratio, circumpapillary retinal nerve fibre layer thickness and MT. There was no significant relationship between the mtDNA/nDNA ratio and MT in patients with OAG overall or the female patients with OAG, but there was a significant relationship between the mtDNA/nDNA ratio and MT, temporal-MT and superior-MT in male patients with severe OAG (r=−0.46, p=0.03; r=−0.51, p=0.02; r=−0.61, p<0.01, respectively). Furthermore, we found that the mtDNA/nDNA ratio was an independent contributor to temporal-MT and superior-MT in these patients (p<0.01 and p=0.03, respectively).ConclusionWe found that there was a significant relationship between the mtDNA/nDNA ratio and MT in male patients with severe OAG, suggesting that the mtDNA/nDNA ratio may be a new biomarker in glaucoma and may help research on the vulnerability of these patients to mitochondrial dysfunction.
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30
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Bianco A, Bisceglia L, De Caro MF, Galeandro V, De Bonis P, Tullo A, Zoccolella S, Guerriero S, Petruzzella V. Leber's hereditary optic neuropathy, intellectual disability and epilepsy presenting with variable penetrance associated to the m.3460G >A mutation and a heteroplasmic expansion of the microsatellite in MTRNR1 gene - case report. BMC MEDICAL GENETICS 2018; 19:129. [PMID: 30053855 PMCID: PMC6062935 DOI: 10.1186/s12881-018-0644-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 07/12/2018] [Indexed: 01/07/2023]
Abstract
Background Leber’s hereditary optic neuropathy (LHON) associated with mutations in mitochondrial DNA (mtDNA) typically manifests only optic nerve involvement but in some patients may develop additional neurological complications. The cause of this association is not clear. Case presentation We present a case of a 24-year-old male with a history of subacute, painless, and rapidly progressive bilateral vision loss. We performed ophthalmological, neurological and neuropsychological investigations in the proband and his LHON family. The proband showed optic neuropathy, epilepsy, migraine, and intellectual disability; all the maternal relatives did not manifest optic neuropathy but a moderate to severe intellectual disability. Genetic screening revealed a novel association of the LHON m.3460G > A primary mutation with the m.T961delT + C(n)ins within the mitochondrial encoded 12S RNA (MTRNR1) gene which segregates with the intellectual disability through the maternal branch of the family. We also found a significant increase of mtDNA content in all the unaffected homo/heteroplasmic mutation carriers with respect to either affected or control subjects. Conclusion This is the first case reporting the co-segregation of a mutation in MTRNR1 gene with a LHON primary mutation, which may be a risk factor of the extraocular signs complicating LHON phenotype. In addition, the data herein reported, confirmed that the key factor modulating the penetrance of optic atrophy in the family is the amount of mtDNA. Electronic supplementary material The online version of this article (10.1186/s12881-018-0644-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Angelica Bianco
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy
| | - Luigi Bisceglia
- Ospedale Casa Sollievo della Sofferenza IRCCS, UOC Genetica Medica, San Giovanni Rotondo, Italy
| | - Maria Fara De Caro
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy
| | - Valeria Galeandro
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy
| | - Patrizia De Bonis
- Ospedale Casa Sollievo della Sofferenza IRCCS, UOC Genetica Medica, San Giovanni Rotondo, Italy
| | - Apollonia Tullo
- Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari, IBIOM - CNR - Via G, Amendola 165/A, 70126, Bari, Italy
| | - Stefano Zoccolella
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy
| | - Silvana Guerriero
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy
| | - Vittoria Petruzzella
- Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, Università degli Studi Aldo Moro, Piazza G. Cesare, 70124, Bari, Italy.
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31
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Finsterer J, Zarrouk-Mahjoub S. Phenotypic manifestations of the m.8969G>A variant. Neurogenetics 2018; 19:131-132. [DOI: 10.1007/s10048-018-0543-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 02/17/2018] [Indexed: 10/17/2022]
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32
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Emperador S, Vidal M, Hernández-Ainsa C, Ruiz-Ruiz C, Woods D, Morales-Becerra A, Arruga J, Artuch R, López-Gallardo E, Bayona-Bafaluy MP, Montoya J, Ruiz-Pesini E. The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient. Front Neurosci 2018; 12:61. [PMID: 29479304 PMCID: PMC5811516 DOI: 10.3389/fnins.2018.00061] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 01/24/2018] [Indexed: 11/13/2022] Open
Abstract
The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.
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Affiliation(s)
- Sonia Emperador
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Mariona Vidal
- Servicio de Oftalmología Pediátrica, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Carmen Hernández-Ainsa
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - Cristina Ruiz-Ruiz
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
| | - Daniel Woods
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
| | - Ana Morales-Becerra
- Servicio de Oftalmología Pediátrica, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Jorge Arruga
- Servicio de Oftalmología, Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Rafael Artuch
- Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), Barcelona, Spain.,Servicio de Bioquímica, Hospital Institut de Recerca Sant Joan de Déu, Barcelona, Spain
| | - Ester López-Gallardo
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - M Pilar Bayona-Bafaluy
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - Julio Montoya
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Eduardo Ruiz-Pesini
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.,Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), Barcelona, Spain.,Fundación ARAID, Zaragoza, Spain
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Abstract
PURPOSE OF REVIEW Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments. RECENT FINDINGS LHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY LHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.
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Caporali L, Maresca A, Capristo M, Del Dotto V, Tagliavini F, Valentino ML, La Morgia C, Carelli V. Incomplete penetrance in mitochondrial optic neuropathies. Mitochondrion 2017; 36:130-137. [PMID: 28716668 DOI: 10.1016/j.mito.2017.07.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 06/27/2017] [Accepted: 07/13/2017] [Indexed: 01/06/2023]
Abstract
Incomplete penetrance characterizes the two most frequent inherited optic neuropathies, Leber's Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA), due to genetic errors in the mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA), respectively. For LHON, compelling evidence has accumulated on the complex interplay of mtDNA haplogroups and environmental interacting factors, whereas the nDNA remains essentially non informative. However, a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number, possibly driven by a permissive nDNA background, is documented in LHON; when successful it maintains unaffected the mutation carriers, but in some individuals it might be hampered by tobacco smoking or other environmental factors, resulting in disease onset. In females, mitochondrial biogenesis is promoted and maintained within the compensatory range by estrogens, partially explaining the gender bias in LHON. Concerning DOA, none of the above mechanisms has been fully explored, thus mtDNA haplogroups, environmental factors such as tobacco and alcohol, and further nDNA variants may all participate as protective factors or, on the contrary, favor disease expression and severity. Next generation sequencing, complemented by transcriptomics and proteomics, may provide some answers in the next future, even if the multifactorial model that seems to apply to incomplete penetrance in mitochondrial optic neuropathies remains problematic, and careful stratification of patients will play a key role for data interpretation. The deep understanding of which factors impinge on incomplete penetrance may shed light on the pathogenic mechanisms leading to optic nerve atrophy, on their possible compensation and, thus, on development of therapeutic strategies.
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Affiliation(s)
- Leonardo Caporali
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
| | - Alessandra Maresca
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
| | | | - Valentina Del Dotto
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Francesca Tagliavini
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy
| | - Maria Lucia Valentino
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Chiara La Morgia
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
| | - Valerio Carelli
- IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.
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Catarino CB, Klopstock T. Use of Idebenone for the Treatment of Leber’s Hereditary Optic Neuropathy. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2017. [DOI: 10.1177/2326409817731112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Claudia B. Catarino
- Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany
- German Network for Mitochondrial Disorders (mitoNET), Munich, Germany
| | - Thomas Klopstock
- Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany
- German Network for Mitochondrial Disorders (mitoNET), Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
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