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Mitochondrial donation (MD) techniques (A) Maternal spindle transfer (MST). (B) Pronuclear transfer (PNT). Both methods involve the removal of nuclear genetic material from patient and donor oocytes either pre-or post-fertilization. The nuclear genetic material from the patient oocyte or zygote is
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Mitochondrial DNA (mtDNA) is a multi-copy genome whose cell copy number varies depending on tissue type. Mutations in mtDNA can cause a wide spectrum of diseases. Mutated mtDNA is often found as a subset of the total mtDNA population in a cell or tissue, a situation known as heteroplasmy. As mitochondrial dysfunction only presents after a certain l...
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Context 1
... use of maternal spindle transfer (MST) to prevent transmission of mtDNA disease was first reported in [25]. In this study, rhesus macaque oocytes at the metaphase II stage of meiosis underwent spindle-chromosomal transfer to an enucleated donor oocyte ( Figure 1A). Following this, the reconstructed oocytes were fertilized, cultured to the blastocyst stage and transferred to the uterus of female macaques. ...
Context 2
... transfer (PNT) was originally developed in 1983 [29] and involves removal of the pronuclei in a membrane-bound karyoplast from a fertilized zygote and transfer to an enucleated donor zygote ( Figure 1B). The potential for this technique to prevent transmission of mtDNA disease was first demonstrated in mouse embryos car- rying an mtDNA mutation [30], followed by a report using abnormally fertilized human zygotes [31]. ...
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... This could indicate that either a sporadic mutation in one of the mitochondrial genes or an environmental factor is responsible for the observed phenotype. Additionally, it is impossible to completely exclude any mitochondrial mutation, as mutated mtDNA could be present only in a subset of the total mtDNA population in a tissue (heteroplasmy) [58]. It is also important to note that the analysis of sequence data should not be regarded as a final assessment of the entirety of all genes. ...
The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria’s involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD’s pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient (“Non-R”) and another with an unexplained mitochondrial disorder (“Mito”). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient’s data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient’s data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
... This 735 could indicate that either a sporadic mutation in one of the mitochondrial genes, or an 736 environmental factor is responsible for the observed phenotype. Additionally, it is impos-737 sible to completely exclude any mitochondrial mutation, as mutated mtDNA could be 738 present only in a subset of the total mtDNA population in a tissue (heteroplasmy) [48]. It 739 is also important to note that the analysis of sequence data should not be regarded as a 740 final assessment of the entirety of all genes. ...
Background: The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria’s involvement in many mechanisms identified in depression, and high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD’s pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito").
Methods: Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed.
Results: Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential.
Conclusions: The Non-R patient’s data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient’s data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
... It is obvious that the analysis can be better performed using mitochondrial genome in animals in comparison to using nuclear genome due to introns deficiency and limited exposure to recombination and haploid inheritance [1]. Egypt The use of robust primers allows mitochondrial genome recovery [2,3]. Formerly, the researchers performed phylogenetic study mainly on mitochondrial genes encoding ribosomal (12S, 16S) DNA. ...
The current Study intends to study the mitochondrial genome proteins specifically focusing on the distribution of intrinsically disordered regions within these proteins. The UniProt were employed to obtain amino acid sequences of the mitochondrial proteins. Next, the obtained sequences were studied to identify their unique features. We used the PONDR VSL2 algorithm to assess the proteins for any order or disorder. According to study results, mito-chondrial genome proteins were expected to depict unexpected levels of intrinsic disorder. The results also indicated the possibility of presence of 7 intrinsic disorder regions within these proteins. The disordered regions were mostly found to be associated with protein-protein interactions. The research indicated the presence of two to nine molecular recognition features in the assessed mitochondrial proteins. These features included short structure-prone segments, location of mitochondrial proteins inside long disordered regions and the feature of showing disorder-to-order transition during binding. Moreover, such regions were attributed with a number of sites characterized with posttranslational modifications. According to the analysis, there may be many disordered regions present within mitochondrial genome proteins leading to mul-tifunctional nature of mitochondrial genome proteins in the signal transduction pathways where these proteins regulate the cell metabolism pathways.
... The ZFNs technique consists of nucleases containing monomers with Fok1 domains, which allow them to reach the mitochondrial matrix, bind to mtDNA, and selectively cleave lncRNA genes. However, toxic effects and loss of mtDNA copies may be long-term consequences of this therapy (Rai et al., 2018). Similarly, transcription activator-like effector nucleases for mitochondria (mitoTALEN) contain Fok1 restriction endonuclease activity that breaks the double mtDNA after dimerization of specific binding sites such as lncRNA loci (Rai et al., 2018). ...
... However, toxic effects and loss of mtDNA copies may be long-term consequences of this therapy (Rai et al., 2018). Similarly, transcription activator-like effector nucleases for mitochondria (mitoTALEN) contain Fok1 restriction endonuclease activity that breaks the double mtDNA after dimerization of specific binding sites such as lncRNA loci (Rai et al., 2018). ...
Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) produced and AMT/T to treat skin aging and related diseases.
... For heteroplasmic pathogenic mtDNA mutations, OXPHOS deficiency becomes clinically relevant when the mtDNA mutation load exceeds a (tissue)specific threshold, resulting in the manifestation of disease symptoms. Lowering the percentage of mutant mtDNA below this threshold by fusion of mtDNA-mutated myotubes with healthy mesoangioblasts might result in sufficient mitochondrial function within the cell or tissue to consolidate, revert or prevent symptoms [11,12]. This is the basis of our therapeutic strategy. ...
In 25% of patients with mitochondrial myopathies, pathogenic mitochondrial DNA (mtDNA) mutation are the cause. For heteroplasmic mtDNA mutations, symptoms manifest when the mutation load exceeds a tissue-specific threshold. Therefore, lowering the mutation load is expected to ameliorate disease manifestations. This can be achieved by fusing wild-type mesoangioblasts with mtDNA mutant myotubes. We have tested this in vitro for female carriers of the m.3271T>C or m.3291T>C mutation (mutation load >90%) using wild-type male mesoangioblasts. Individual fused myotubes were collected by a newly-developed laser capture microdissection (LCM) protocol, visualized by immunostaining using an anti-myosin antibody. Fusion rates were determined based on male-female nuclei ratios by fluorescently labelling the Y-chromosome. Using combined ‘wet’ and ‘air dried’ LCM imaging improved fluorescence imaging quality and cell yield. Wild-type mesoangioblasts fused in different ratios with myotubes containing either the m.3271T>C or the m.3291T>C mutation. This resulted in the reduction of the mtDNA mutation load proportional to the number of fused wild-type mesoangioblasts for both mtDNA mutations. The proportional reduction in mtDNA mutation load in vitro after fusion is promising in the context of muscle stem cell therapy for mtDNA mutation carriers in vivo, in which we propose the same strategy using autologous wild-type mesoangioblasts.
... Mitochondrial replacement therapy is a method in which nuclear DNA from a mother with a mtDNA mutation is transferred to an oocyte or zygote that contains normal mtDNA from a healthy donor [75,76]. There have been several reports showing the feasibility of these techniques in human oocytes and that good quality embryos can be produced [77]. ...
Mitochondrial cardiomyopathy (MCM) is characterized by abnormal heart-muscle structure and function, caused by mutations in the nuclear genome or mitochondrial DNA. The heterogeneity of gene mutations and various clinical presentations in patients with cardiomyopathy make its diagnosis, molecular mechanism, and therapeutics great challenges. This review describes the molecular epidemiology of MCM and its clinical features, reviews the promising diagnostic tests applied for mitochondrial diseases and cardiomyopathies, and details the animal and cellular models used for modeling cardiomyopathy and to investigate disease pathogenesis in a controlled in vitro environment. It also discusses the emerging therapeutics tested in pre-clinical and clinical studies of cardiac regeneration.
... More recently, certain base-editing enzymes, such as cytidine deaminases, have also been used to modify specific sequences in the mitochondria [87]. Modified base-editing enzymes and methods for shifting heteroplasmy remain active areas of research and have been extensively reviewed [88][89][90]. ...
Mitochondria are intracellular organelles that utilize nutrients to generate energy in the form of ATP by oxidative phosphorylation. Mitochondrial DNA (mtDNA) in humans is a 16,569 base pair double-stranded circular DNA that encodes for 13 vital proteins of the electron transport chain. Our understanding of the mitochondrial genome’s transcription, translation, and maintenance is still emerging, and human pathologies caused by mtDNA dysfunction are widely observed. Additionally, a correlation between declining mitochondrial DNA quality and copy number with organelle dysfunction in aging is well-documented in the literature. Despite tremendous advancements in nuclear gene-editing technologies and their value in translational avenues, our ability to edit mitochondrial DNA is still limited. In this review, we discuss the current therapeutic landscape in addressing the various pathologies that result from mtDNA mutations. We further evaluate existing gene therapy efforts, particularly allotopic expression and its potential to become an indispensable tool for restoring mitochondrial health in disease and aging.
... The frequency of mtDNA deletions and mutations increases with age in human somatic tissues [97], with the substitution rate of mtDNA being an order of magnitude higher than that of the nuclear DNA (nDNA) mutations [98,99]. While these alterations do not result in a significant change in the absolute copy number, they reduce respiratory activity and are considered to be important drivers of aging [100][101][102] and the pathophysiology of AD [103][104][105]. The common mtDNA 5 kb deletion is increased > 15 times in AD brains [106,107] and somatic mtDNA control region (CR) mutations are increased 73% in AD brains [108]. ...
Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments avail- able for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initi- ation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mito- chondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mito- chondrial systems biology. We review evidence for mitochondrial impairments ranging from mito- chondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expres- sion, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dy- namics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could poten- tially alter the course of this progressive, heterogeneous Disease while being cognizant that success- ful future therapeutics may require a combinatorial approach.
... Dietary supplements are given frequently but are of uncertain efficacy. 22 There are, however, several emerging treatments, 23 24 but assessment of treatment efficacy in clinical trials is difficult due on December 6, 2021 by guest. Protected by copyright. ...
Background
Large-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.
Methods
A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.
Results
A total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).
Conclusion
Our study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.
... In the case of spindle transfer, the patient's oocyte nucleus is removed and inserted into the unfertilized oocyte of the donor who previously had the nucleus removed [10]. ...
Mitochondrial diseases are sporadic and very serious. The causes of these diseases are the mutations of the mitochondrial(mt) DNA (deoxyribonucleic acid) which is of maternal origin. The phenotypic variability of mitochondrial disease is determined by the simultaneous presence of normal and mutant mt DNA in the cytoplasm, a process called heteroplasmy. We present a case of Leigh syndrome in a twin pregnancy after in vitro fertilization (IVF). The two-month-old infant extracted by cesarean section at thirty-eight weeks of gestation was admitted to the hospital for worsening respiratory symptoms. The symptoms had started seven days before with fever and difficulty breathing; marked metabolic acidosis was discovered at the lumbar puncture that was done at admission in the hospital. We sent the patient to genetic testing due to congenital lactic acidosis. Leigh syndrome was strongly suspected. First, he had the sequencing analysis of the genes in Leigh syndrome and mitochondrial encephalopathy panel and a heterozygous variant of uncertain significance in the COQ8A gene, also known as ADCK3, c.521C>A p was found (Thr174Lys). Unfortunately, the infant died in the hospital due to cardiorespiratory arrest. The parents are now considering having another IVF procedure, and we are discussing all the possible variants with them.
