Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality

Yamada, Mitsutoshi; Sato, Suguru; Ooka, Reina; Akashi, Kazuhiro; Nakamura, Akihiro; Miyado, Kenji; Akutsu, Hidenori; Tanaka, Mamoru

doi:10.1002/rmb2.12356

Cited by 11 publications

(5 citation statements)

References 48 publications

(96 reference statements)

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“…Mitochondrial replacement therapy by ooplasm transfer could be a potential treatment for advanced maternal age. However, ooplasm transfer includes medical risks and ethical objections and is therefore not yet a good treatment option for advanced maternal age ( Yamada et al , 2021 ). Other possible treatment options include enhancing the depleted NAD + pool or correcting glutathione deficiency in oocytes of advanced maternal age.…”

Section: Discussionmentioning

confidence: 99%

Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction

Smits,

Schomakers,

van Weeghel

et al. 2023

Human Reproduction

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STUDY QUESTION Are human ovarian aging and the age-related female fertility decline caused by oxidative stress and mitochondrial dysfunction in oocytes? SUMMARY ANSWER We found oxidative damage in oocytes of advanced maternal age, even at the primordial follicle stage, and confirmed mitochondrial dysfunction in such oocytes, which likely resulted in the use of alternative energy sources. WHAT IS KNOWN ALREADY Signs of reactive oxygen species-induced damage and mitochondrial dysfunction have been observed in maturing follicles, and even in early stages of embryogenesis. However, although recent evidence indicates that also primordial follicles have metabolically active mitochondria, it is still often assumed that these follicles avoid oxidative phosphorylation to prevent oxidative damage in dictyate arrested oocytes. Data on the influence of ovarian aging on oocyte metabolism and mitochondrial function are still limited. STUDY DESIGN, SIZE, DURATION A set of 39 formalin-fixed and paraffin-embedded ovarian tissue biopsies were divided into different age groups and used for immunofluorescence analysis of oxidative phosphorylation activity and oxidative damage to proteins, lipids, and DNA. Additionally, 150 immature oocytes (90 germinal vesicle oocytes and 60 metaphase I oocytes) and 15 cumulus cell samples were divided into different age groups and used for targeted metabolomics and lipidomics analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian tissues used for immunofluorescence microscopy were collected through PALGA, the nationwide network, and registry of histo- and cytopathology in The Netherlands. Comprehensive metabolomics and lipidomics were performed by liquid–liquid extraction and full-scan mass spectrometry, using oocytes and cumulus cells of women undergoing ICSI treatment based on male or tubal factor infertility, or fertility preservation for non-medical reasons. MAIN RESULTS AND THE ROLE OF CHANCE Immunofluorescence imaging on human ovarian tissue indicated oxidative damage by protein and lipid (per)oxidation already at the primordial follicle stage. Metabolomics and lipidomics analysis of oocytes and cumulus cells in advanced maternal-age groups demonstrated a shift in the glutathione-to-oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine, and pyrimidine depletion, while glycolysis substrates and glutamine accumulated, with age. Oocytes from women of advanced maternal age appeared to use alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly ATP which showed increased production in cumulus cells. LIMITATIONS, REASONS FOR CAUTION The immature oocytes used in this study were all subjected to ovarian stimulation with high doses of follicle-stimulating hormones, which might have concealed some age-related differences. WIDER IMPLICATIONS OF THE FINDINGS Further studies on how to improve mitochondrial function, or lower oxidative damage, in oocytes from women of advanced maternal age, for instance by supplementation of NAD+ precursors to promote mitochondrial biogenesis, are warranted. In addition, supplementing the embryo medium of advanced maternal-age embryos with such compounds could be a treatment option worth exploring. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Amsterdam UMC. The authors declare to have no competing interests. TRIAL REGISTRATION NUMBER N/A.

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Section: Discussionmentioning

confidence: 99%

Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction

Smits,

Schomakers,

van Weeghel

et al. 2023

Human Reproduction

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“…This research on mitochondrial intercellular transfer between different cell types provides a potential therapeutic target to improve mitochondrial biogenesis in AD patients. It is conceivable that a revolutionary transplant technique could heal damaged organs, offering a glimmer of hope to those struggling to survive events such as cardiac arrests, strokes, and the like [194,209]. Supplementation of exogenous healthy mitochondria to replace damaged mitochondria improved cellular bioenergetics, reversed excessive ROS production, and restored mitochondrial function [210,211].…”

Section: Involvement Of the Mitochondria In Diseases Rare And Notmentioning

confidence: 99%

Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease

Atlante

Valenti

2023

CIMB

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Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their central role in energy metabolism, these chemiosmotic machines that synthesize ATP are known as the only maternally inherited organelles with their own genome, where mutations can cause diseases, opening up the field of mitochondrial medicine. More recently, the omics era has highlighted mitochondria as biosynthetic and signaling organelles influencing the behaviors of cells and organisms, making mitochondria the most studied organelles in the biomedical sciences. In this review, we will especially focus on certain ‘novelties’ in mitochondrial biology “left in the shadows” because, although they have been discovered for some time, they are still not taken with due consideration. We will focus on certain particularities of these organelles, for example, those relating to their metabolism and energy efficiency. In particular, some of their functions that reflect the type of cell in which they reside will be critically discussed, for example, the role of some carriers that are strictly functional to the typical metabolism of the cell or to the tissue specialization. Furthermore, some diseases in whose pathogenesis, surprisingly, mitochondria are involved will be mentioned.

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“…Except for the fertilization process, various types of MRTs involve replacing the maternal nuclear DNA with the nuclear DNA in the donor's cells. Despite the successful results of MRT operations [16], there have been debatable outcomes, such as the reversion of mutated DNA [226,227] and other ethical concerns [228]. Ultimately, the FDA has announced that performing MRT is not permitted in the USA.…”

Section: Clinical Approach Using Non-chemical Treatmentsmentioning

confidence: 99%

Clinical Approaches for Mitochondrial Diseases

Hong,

Kim,

Kim

et al. 2023

Cells

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Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit proteins that make up the crucial system required to perform ‘oxidative phosphorylation (OX PHOS)’, which are expressed by the mitochondria’s self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. Mitochondrial DNA replicates almost autonomously, independent of the nucleus, and its heredity follows a non-Mendelian pattern, exclusively passing from mother to children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences of various types of mtDNA mutations, including insertions, deletions, and single base-pair mutations, are studied to reveal their relationship to mitochondrial diseases. Most mitochondrial diseases exhibit fatal symptoms, leading to ongoing therapeutic research with diverse approaches such as stimulating the defective OXPHOS system, mitochondrial replacement, and allotropic expression of defective enzymes. This review provides detailed information on two topics: (1) mitochondrial diseases caused by mtDNA mutations, and (2) the mechanisms of current treatments for mitochondrial diseases and clinical trials.

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Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality

Cited by 11 publications

References 48 publications

Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction

Human ovarian aging is characterized by oxidative damage and mitochondrial dysfunction

Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease

Clinical Approaches for Mitochondrial Diseases

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