Maternal transmission of mitochondrial diseases

Chiaratti, Marcos Roberto; Macabelli, Carolina Habermann; Neto, José tDjaci Augusto; Grejo, Mateus P.; Pandey, Anand Kumar; Perecin, Felipe; Collado, Maite del

doi:10.1590/1678-4685-gmb-2019-0095

Cited by 18 publications

(7 citation statements)

References 186 publications

(269 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Drosophila mitochondria contain multiple copies of circular DNA (mtDNA), which encode tRNAs, rRNAs, and polypeptides important for oxidative phosphorylation. The study of mitochondrial genes is important, because mutations in mtDNA can cause devastating human disorders, such as Leber's hereditary optic neuropathy, which causes blindness [77][78][79]. To modify CRISPR/Cas13 applications for mitochondrial-encoded transcripts, we added a sequence encoding an N-terminal mitochondrial targeting peptide derived from the nuclear-encoded translocase of the inner mitochondrial membrane 23 (tim23) gene.…”

Section: Targeting Mitochondrial Rnas Via Cas13mentioning

confidence: 99%

A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila

et al. 2020

View full text Add to dashboard Cite

Advances in CRISPR technology have immensely improved our ability to manipulate nucleic acids, and the recent discovery of the RNA-targeting endonuclease Cas13 adds even further functionality. Here, we show that Cas13 works efficiently in Drosophila, both ex vivo and in vivo. We test 44 different Cas13 variants to identify enzymes with the best overall performance and show that Cas13 could target endogenous Drosophila transcripts in vivo with high efficiency and specificity. We also develop Cas13 applications to edit mRNAs and target mitochondrial transcripts. Our vector collection represents a versatile tool collection to manipulate gene expression at the post-transcriptional level.

show abstract

Section: Targeting Mitochondrial Rnas Via Cas13mentioning

confidence: 99%

A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila

et al. 2020

View full text Add to dashboard Cite

show abstract

“…One explanation is the stochastic loss of paternal mtDNA in a zygote after fertilization due to dilution (Birky, 1983). In animals, a mature sperm carries just a few copies of mtDNA, in contrast, an oocyte contains 10 5 to 10 8 copies of mtDNA (Jansen and de Boer, 1998;Chiaratti et al, 2020). Therefore, the sperm mtDNA heteroplasmy in zygotes or preimplantation embryos is well below the detection levels by most existing methods (Santos et al, 2006;Wu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Germline transmission of donor, maternal and paternal mtDNA in primates

Dyken

Darby

et al. 2020

Human Reproduction

View full text Add to dashboard Cite

STUDY QUESTION What are the long-term developmental, reproductive and genetic consequences of mitochondrial replacement therapy (MRT) in primates? SUMMARY ANSWER Longitudinal investigation of MRT rhesus macaques (Macaca mulatta) generated with donor mtDNA that is exceedingly distant from the original maternal counterpart suggest that their growth, general health and fertility is unremarkable and similar to controls. WHAT IS KNOWN ALREADY Mitochondrial gene mutations contribute to a diverse range of incurable human disorders. MRT via spindle transfer in oocytes was developed and proposed to prevent transmission of pathogenic mtDNA mutations from mothers to children. STUDY DESIGN, SIZE, DURATION The study provides longitudinal studies on general health, fertility as well as transmission and segregation of parental mtDNA haplotypes to various tissues and organs in five adult MRT rhesus macaques and their offspring. PARTICIPANTS/MATERIALS, SETTING, METHODS MRT was achieved by spindle transfer between metaphase II oocytes from genetically divergent rhesus macaque populations. After fertilization of oocytes with sperm, heteroplasmic zygotes contained an unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mitochondrial (mt)DNA. MRT monkeys were grown to adulthood and their development and general health was regularly monitored. Reproductive fitness of male and female MRT macaques was evaluated by time-mated breeding and production of live offspring. The relative contribution of donor, maternal, and paternal mtDNA was measured by whole mitochondrial genome sequencing in all organs and tissues of MRT animals and their offspring. MAIN RESULTS AND THE ROLE OF CHANCE Both male and female MRT rhesus macaques containing unequal mixture of three parental genomes, i.e. donor (≥97%), maternal (≤3%), and paternal (≤0.1%) mtDNA reached healthy adulthood, were fertile and most animals stably maintained the initial ratio of parental mtDNA heteroplasmy and donor mtDNA was transmitted from females to offspring. However, in one monkey out of four analyzed, initially negligible maternal mtDNA heteroplasmy levels increased substantially up to 17% in selected internal tissues and organs. In addition, two monkeys showed paternal mtDNA contribution up to 33% in selected internal tissues and organs. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Conclusions in this study were made on a relatively low number of MRT monkeys, and on only one F1 (first generation) female. In addition, monkey MRT involved two wildtype mtDNA haplotypes, but not disease-relevant variants. Clinical trials on children born after MRT will be required to fully determine safety and efficacy of MRT for humans. WIDER IMPLICATIONS OF THE FINDINGS Our data show that MRT is compatible with normal postnatal development including overall health and reproductive fitness in nonhuman primates without any detected adverse effects. ‘Mismatched’ donor mtDNA in MRT animals even from the genetically distant mtDNA haplotypes did not cause secondary mitochondrial dysfunction. However, carry-over maternal or paternal mtDNA contributions increased substantially in selected internal tissues / organs of some MRT animals implying the possibility of mtDNA mutation recurrence. STUDY FUNDING/COMPETING INTEREST(S) This work has been funded by the grants from the Burroughs Wellcome Fund, the National Institutes of Health (RO1AG062459 and P51 OD011092), National Research Foundation of Korea (2018R1D1A1B07043216) and Oregon Health & Science University institutional funds. The authors declare no competing interests.

show abstract

“…mtDNA is present in stroma and is only transmitted through the female germline [ 4 ]. Sperm have only 100 mtDNA copies compared to eggs, which have 150,000 [ 5 ].…”

Section: Mitochondrial Dna (Mtdna)mentioning

confidence: 99%

A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility

Amor

Hammadeh

2022

Genes

View full text Add to dashboard Cite

According to current estimates, infertility affects one in four couples trying to conceive. Primary or secondary infertility can be due either to both partners or only to the man or the woman. Up to 15% of infertility cases in men can be attributed to genetic factors that can lead to irreversible partial or complete spermatogenic arrest. The increased use of assisted reproductive technology (ART) has provided not only insights into the causes of male infertility but also afforded a diagnostic tool to detect and manage this condition among couples. Genes control a variety of physiological attributes, such as the hypothalamic–pituitary–gonadal axis, development, and germ cell differentiation. In the era of ART, it is important to understand the genetic basis of infertility so as to provide the most tailored therapy and counseling to couples. Genetic factors involved in male infertility can be chromosome abnormalities or single-gene disorders, mitochondrial DNA (mtDNA) mutations, Y-chromosome deletions, multifactorial disorders, imprinting disorders, or endocrine disorders of genetic origin. In this review, we discuss the role of mitochondria and the mitochondrial genome as an indicator of sperm quality and fertility.

show abstract

Maternal transmission of mitochondrial diseases

Cited by 18 publications

References 186 publications

A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila

A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila

Germline transmission of donor, maternal and paternal mtDNA in primates

A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility

Contact Info

Product

Resources

About