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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results.

\"For over a century, we've accepted the scientific consensus that cancer results from genetic disease due to chromosomal damage in cell nuclei. But what if cancer isn't a genetic disease after all? What if scientists are chasing a flawed paradigm, and cancer isn't a disease of damaged DNA but rather of defective metabolism as a result of mitochondrial dysfunction? What if that [theory] could revolutionize our understanding of other diseases as well--and show us a radical new path to optimal health?\"-- Provided by publisher.

Mitochondrial replacement techniques (MRTs) usually aim to prevent the genetic transmission of maternally inherited mitochondrial diseases. Until now, only the UK and Australia have implemented specific legal regulations of MRTs. In both countries, clinical trials on these techniques are only permissible for cases with a high risk of severe mitochondrial disease in the offspring. However, these techniques can also be applied to treat infertility, especially for older women with impaired oocyte quality. In some countries without legal regulation of these techniques, MRTs are already offered for this purpose. Yet, this application of MRTs has received insufficient attention in the bioethical literature so far.In this paper, I examine whether there are ethical reasons to prohibit trials on MRTs in the context of infertility when they are permitted for preventing mitochondrial disease. Allowing MRTs in one context but not the other might be justified either because their application in the context of mitochondrial disease (1) is supported by a more convincing evidence base, (2) has a higher potential benefit or (3) has a lower risk. I compare both applications of MRTs with respect to these three factors. I conclude that there is no convincing reason to prohibit clinical trials on MRTs for infertility when they are permitted in the context of mitochondrial disease.

Mitochondria are currently of great interest to scientists. The role of mitochondrial DNA (mtDNA) mutations has been proven in the genesis of more than 200 pathologies, which are called mitochondrial disorders. Therefore, the study of mitochondria and mitochondrial DNA is of great interest not only for understanding cell biology but also for the treatment and prevention of many mitochondria-related pathologies. There are two main trends of mitochondrial therapy: mitochondrial replacement therapy (MRT) and mitochondrial transplantation therapy (MTT). Also, there are two main categories of MRT based on the source of mitochondria. The heterologous approach includes the following methods: pronuclear transfer technique (PNT), maternal spindle transfer (MST), Polar body genome transfer (PBT) and germinal vesicle transfer (GVT). An alternative approach is the autologous method. One promising autologous technique was the autologous germline mitochondrial energy transfer (AUGMENT), which involved isolating oogonial precursor cells from the patient, extracting their mitochondria, and then injecting them during ICSI. Transmission of defective mtDNA to the next generation can also be prevented by using these approaches. The development of a healthy child, free from genetic disorders, and the prevention of the occurrence of lethal mitochondrial disorders are the main tasks of this method. However, a number of moral, social, and cultural objections have restricted its exploration, since humanity first encountered the appearance of a three-parent baby. Therefore, this review summarizes the causes of mitochondrial diseases, the various methods involved in MRT and the results of their application. In addition, a new technology, mitochondrial transplantation therapy (MTT), is currently being actively studied. MTT is an innovative approach that involves the introduction of healthy mitochondria into damaged tissues, leading to the replacement of defective mitochondria and the restoration of their function. This technology is being actively studied in animals, but there are also reports of its use in humans. A bibliographic review in PubMed and Web of Science databases and a search for relevant clinical trials and news articles were performed. A total of 81 publications were selected for analysis. Methods of MRT procedures were reviewed, their risks described, and the results of their use presented. Results of animal studies of the MTT procedure and attempts to apply this therapy in humans were reviewed. MRT is an effective way to minimize the risk of transmission of mtDNA-related diseases, but it does not eliminate it completely. There is a need for global legal regulation of MRT. MTT is a new and promising method of treating damaged tissues by injecting the body’s own mitochondria. The considered methods are extremely good in theory, but their clinical application in humans and the success of such therapy remain a question for further study.

It has been suggested that deleterious interactions between the mitochondrial and nuclear genomes could pose a problem for mitochondrial replacement therapy (MRT). This is because the mitochondrial genome is placed in a novel nuclear environment using this technique. In contrast, it is inherited with half the mother’s genome during normal reproduction, a genome that it is relatively compatible with, since the mother is alive. Here, I review the evidence of whether mito-nuclear interactions are likely to pose a problem for MRT. The majority of the available experimental evidence, both in humans and other species, suggests that MRT is not harmful. These results are consistent with population genetic theory, which predicts that deleterious mito-nuclear interactions are unlikely to be much more prevalent in individuals born to MRT than normal reproduction, particularly in a species such as humans with low population differentiation. This is because selection is unlikely to be strong enough to establish significant linkage disequilibrium between the mitochondrial and nuclear genomes. These results are supported by a meta-analysis of 231 cases, from a variety of animals, in which the mitochondrial DNA (mtDNA) from one strain has been introgressed into the nuclear background of another strain of the same species. Overall, there is little tendency for introgression of mtDNA to be harmful.

Mitochondrial DNA is maternally inherited, and pathogenic mutations cause a range of life-limiting conditions. Recent studies indicate that transmission of pathogenic mutations may be prevented by reproductive technologies designed to replace the mitochondria in eggs from affected women.

Mitochondrial replacement is provided in England and Wales to women with mitochondrial disease seeking to have an unaffected child. However, the use of this technique for the treatment of a different condition — infertility — is unproven and yet is being offered at fertility clinics worldwide.

Background Mitochondrial Diseases (MDs) refers to a heterogeneous group of inherited metabolic disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS) caused by pathogenic mitochondrial DNA or nuclear DNA variants. As mitochondria are pivotal for cell bioenergetics, MDs could potentially affect multisystem, leaving a devastating and life-threatening impact. The treatment of MDs present significant challenges due to the complexity of the disease and the wide heterogeneity of its molecular defects. Thus, the need for innovative and more comprehensive therapeutic approaches is evident. Methods This longitudinal, open-label study was a pilot trial involving 9 paediatric MD patients, aiming to gain a better understanding on the impact of hydroxytyrosol (HT) on the clinical outcomes of MD patients and to assess the feasibility and logistics of using HT as a dietary supplement for MD patients. Subjects received HT daily as dietary supplements for 12 months. Following this period, patients were then randomly assigned to either discontinue HT or continue receiving HT as their dietary supplements for an additional 6 months. Outcome measures that were assessed included the International Paediatric Mitochondrial Disease Scores, biochemical parameters, and quality of life assessments. Results Among the outcome measures assessed, HT supplementation demonstrated the most considerable impact on improving the health-related quality of life according to the PedsQL scoring system and potential effects on a subgroup of MD patients with Mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS). Discussion This study demonstrated that HT supplementation resulted in improvement in health-related quality of life in MD patients, while the subgroup of MELAS patients showed additional potential beneficial effect from HT use. As a pilot trial, this study importantly highlighted HT’s tolerability in MD patients, which would facilitate trials of larger scale to be performed in the future. Conclusion This study highlights the use of HT as a health supplement and its potential therapeutic effects in paediatric patients diagnosed with MDs, especially in MELAS patients. The results lay the foundation for future large-scale clinical trials. Consequently, further clinical intervention studies and investigations into HT’s potential therapeutic mechanisms at the molecular and intercellular levels are strongly encouraged.

Background Mitochondrial donation (MD) is a reproductive technique that aims to allow individuals at-risk of having a child with mitochondrial DNA disease avoid this outcome. Research to inform possible clinical use of MD is underway in Australia and births following the use of this technique have been announced in the United Kingdom. However, how the availability of MD will be funded in the mid- to long-term remains uncertain. One factor impacting funding decisions is public sentiment, yet there is scant evidence globally regarding attitudes toward MD funding. We sought to discern attitudes of informed members of the Australian public to how the provision of MD should be funded. Methods We held three community juries to gauge public views on how MD should be funded. A community jury involves providing a diverse group of citizens with expert testimony and facilitating deliberation to arrive at a position. Results Forty-two jurors participated across three juries. All juries voted by majority to support public funding for MD. Each jury made slightly different funding choices: one preferred full public funding, another preferred co-payment, while the third was divided among full public funding, co-payment, and no public funding. Reasons in favour of public funding comprised value for money, equity (i.e., the fair and just distribution of MD) and promoting innovation. Reasons against were opportunity cost, that MD wasn’t necessary, and ethical objections to MD. Jurors also devised conditions for future funding: external review, capped services, better funding for alternative interventions and means testing. Conclusions Should the current Australian MD research trial enable clinical provision, assuming that our participants’ views are consistent with those of most Australians when informed of the trade-offs, benefits and costs, then it is likely that there will be strong public support for governments to fund access. However, some people may object to this expenditure.