The advances and new technologies for the study of mitochondrial diseases

Abstract

Genetic mitochondrial disorders are responsible for the most common inborn errors of metabolism, caused by mutations in either nuclear genes or in mitochondrial DNA. This article presents the prokaryotic origin of the organelle and the relation between nuclear and mitochondrial genomes, as well as current evolutionary models for such mechanisms. It also addresses the structure of mitochondrial genes, their expression pattern, clinical features of gene defects, risk of transmission and current techniques to avoid these events in assisted human reproduction. Finally, it discusses the ethical implications of these possibilities.

Effects of nuclear respiratory factor‑1 on apoptosis and mitochondrial dysfunction induced by cobalt chloride in H9C2 cells

“…Mitochondrial DNA (mtDNA) is a double-stranded circular DNA containing 37 genes and encoding 13 polypeptides that are involved in the synthesis of ATP (15,16). Although ~1,500 proteins participate in the regulation of mitochondrial structure and function, because of the limited coding capacity of mtDNA, <1% of these proteins are encoded by mitochondria, and the remaining proteins are encoded by nuclear genes (17–19). Therefore, the biological processes of mitochondria are regulated by both mitochondrial and nuclear genes.…”

The special considerations of gene therapy for mitochondrial diseases

“…However, no matter the specific approach employed, they all result in offspring that is genetically related to the patient (mother) and father at the level of the nuclear genome, but who will carry mtDNA from the oocyte donor and thus suffer none of the health consequences of the patient's mtDNA mutation. 59 Beyond the novel ethical issues raised by the notion of this kind of "three-parent" baby, there is a practical safety concern with MRT regarding the amount of mutated mtDNA carried over from the patient during the process of transferring the nuclear material. No matter how precisely done, there is always some cytoplasmic material carried over when the nuclear material is extracted and transferred.…”

“…No matter how precisely done, there is always some cytoplasmic material carried over when the nuclear material is extracted and transferred. So long as appropriate care is taken to minimize the amount of cytoplasmic carry-over (in the most optimized methods, less than 2%), 59 the resulting heteroplasmy appears to be quite low. 60 This is also borne out by reports from individuals who were born as a result of ooplasmic transplantation (an earlier and less sophisticated alternative to MRT), who appear to be largely normal in terms of health and cognitive abilities.…”

Mitochondria and Their Role in Human Reproduction

“…Ultimately, MRT involves transferring the nuclear genome from a patient's oocyte with mutated mtDNA to a healthy enucleated oocyte, producing a conceptus with DNA from the mother's nuclear genome, the father's nuclear genome, and an oocyte donor's mitochondrial genome (Bianco and Montagna, 2016).…”

“…It appears that if pathogenic mtDNA represents <5% of the embryo's mtDNA, the recurrence risk of mtDNA diseases in subsequent generations is significantly reduced (Schandera and Mackey, 2016). In fact, in an early preclinical study, an optimized PNT method was shown to reduce mtDNA carryover to <2% in most blastocysts (79%), and there was no more than 5% heterogeneity in any blastocyst (Bianco and Montagna, 2016). mtDNA heterogeneity was considered stable in most of the embryonic stem cell lines derived from reconstructed embryos after ST, although a gradual decrease in mutant mtDNA with reversal of the nuclear donor's haplotype was found in some embryonic stem cells (ESC) lines (Kang et al, 2016).…”