Mitochondria And The Future Of Medicine: The Ke...

Abstract:Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.Keywords: mitochondria; mitochondrial diseases; mitochondrial medicine; mitochondrial dysfunction; mitochondrial transplantation

Mitochondrial DNA is prone to somatic mutations, which are a type of noninherited mutation. Somatic mutations occur in the DNA of certain cells during a person's lifetime and typically are not passed to future generations. There is limited evidence linking somatic mutations in mitochondrial DNA with certain cancers, including breast, colon, stomach, liver, and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).

In this study we identified a previously unknown link between total intracellular ATP levels and Ras1 signaling in C. albicans by characterizing the mechanism by which MB inhibits the C. albicans yeast-to-hypha switch (Fig 9). Interestingly, a recent study in the yeast S. cerevisiae found that dysfunctional mitochondria decrease cAMP-PKA signaling, adhesion production, and filamentous growth further emphasizing that the link between respiratory activity and Ras1-cAMP-PKA signaling is conserved beyond the Candida genus [62]. The same study also showed that the filamentous-growth-specific MAPK pathway is not involved in this signaling as this pathway retained functionality in respiratory-deficient S. cerevisiae yeast cells [62]. Furthermore, while it is not known whether Ras1 signaling is important for filamentation or virulence in C. tropicalis and C. parapsilosis, when grown on YNBAGNP media with and without MB, both Candida species had decreased Ras1 activation state with MB indicating that the link between respiratory activity and Ras1 signaling is conserved across Candida species. However, whether this decrease in Ras1 activation impacts filamentation and virulence of these fungal pathogens needs to be determined in future studies.

Ethicists are also concerned about the potential misuse of mitochondrial transfer. With the recent rise in genome editing technologies such as CRISPR-Cas9, bioethicists worldwide are calling for bans on alterations to genetic information passed on from parent to child. But this is exactly what happens when a daughter is born as a result of mitochondrial transfer; the daughter will carry mitochondrial DNA from a third unknown donor, which she will pass on to all of her future children. And if she has daughters, they will continue to pass on this donor DNA, affecting the genetic information of many generations to come in ways we cannot fully predict. This dilemma brings up an interesting question: should parents of mitochondrial transfer select only male embryos to prevent potentially changing the course of their blood line, or do parents have the right to have children of either sex despite the effect potential future generations

PD is caused by complex interactions between genetic and environmental factors. Mutations in SNCA (α-synuclein), LRRK2 (Leucine Rich Repeat Kinase 2), and VPS35 (VPS35 Retromer Complex Component) cause an autosomal dominant form of mPD whereas mutations in PRKN (Parkin), PINK1 (PTEN-induced kinase 1), and PARK7 (oncogene DJ-1) (among others) are associated with autosomal-recessive mPD (Lill 2016). Although SNCA was the first identified PD-related gene almost 25 years ago it is very rare whereas mutations in LRRK2 are the most frequent cause of mPD (Cookson 2015). The identification of the autosomal-recessive genes PRKN, PINK1, and PARK7 linked the proposed role of mitochondrial dysfunction in the etiology of PD to genetic causes (Exnre et al. 2012). Monogenic causes are often summarized under the umbrella term of mPD even if parkinsonism is only one of the presenting symptoms and only part of a more complex or atypical phenotype (e.g., in DNAJC6 mutation carriers, Table 1) (Puschmann 2013). Whether molecular insights of causative genes for atypical phenotypes provide translatable findings to IPD needs to be critically evaluated (Grünewald et al. 2013; Klein et al. 2007). In addition, several genes were not yet replicated in independent families or populations. Furthermore, most forms are exceedingly rare making it unlikely that specific therapies are being developed. In addition to mPD that follows the rules of Mendelian inheritance, variants in the GBA (Glucosylceramidase Beta) gene are an unequivocal and frequent risk factor for the development of PD and a promising future drug target.

Mitochondrial replacement therapy (MRT), sometimes called mitochondrial donation, is the replacement of mitochondria in one or more cells to prevent or ameliorate disease. MRT originated as a special form of in vitro fertilisation in which some or all of the future baby's mitochondrial DNA (mtDNA) comes from a third party. This technique is used in cases when mothers carry genes for mitochondrial diseases. The therapy is approved for use in the United Kingdom.[1][2] A second application is to use autologous mitochondria to replace mitochondria in damaged tissue to restore the tissue to a functional state. This has been used in clinical research in the United States to treat cardiac-compromised newborns.[3] 59ce067264

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