The objective of this review is to outline existing artificial mitochondria transfer techniques and to describe the future steps necessary to develop new therapeutic applications in medicine. Inspired by the symbiotic origin of mitochondria and by the cell's capacity to transfer these organelles to damaged neighbors, many researchers have developed procedures to artificially transfer mitochondria from one cell to another. The techniques currently in use today range from simple coincubations of isolated mitochondria and recipient cells to the use of physical approaches to induce integration. These methods mimic natural mitochondria transfer. In order to use mitochondrial transfer in medicine, we must answer key questions about how to replicate aspects of natural transport processes to improve current artificial transfer methods. Another priority is to determine the optimum quantity and cell/tissue source of the mitochondria in order to induce cell reprogramming or tissue repair, in both in vitro and in vivo applications. Additionally, it is important that the field explores how artificial mitochondria transfer techniques can be used to treat different diseases and how to navigate the ethical issues in such procedures. Without a doubt, mitochondria are more than mere cell power plants, as we continue to discover their potential to be used in medicine.

/pdf/artificial-mitochondria-transfer-current-challenges-advances-25oxl9zo47.pdf

Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications.

The aim of this review was to provide an evidence-based approach to frequently asked questions relating to the risk of transmitting a maternally inherited mitochondrial disorder (MID). We do not address disorders linked with disturbed mitochondrial DNA (mtDNA) maintenance, causing mtDNA depletion or multiple mtDNA deletions, as these are autosomally inherited. The review addresses questions regarding prognosis, recurrence risks and the strategies available to prevent disease transmission. The clinical and genetic complexity of maternally inherited MIDs represent a major challenge for patients, their relatives and health professionals. Since many of the genetic and pathophysiological aspects of MIDs remain unknown, counselling of affected patients and at-risk family members remains difficult. MtDNA mutations are maternally transmitted or, more rarely, they are sporadic, occurring de novo (~25%). Females carrying homoplasmic mtDNA mutations will transmit the mutant species to all of their offspring, who may or may not exhibit a similar phenotype depending on modifying, secondary factors. Females carrying heteroplasmic mtDNA mutations will transmit a variable amount of mutant mtDNA to their offspring, which can result in considerable phenotypic heterogeneity among siblings. The majority of mtDNA rearrangements, such as single large-scale deletions, are sporadic, but there is a small risk of recurrence (~4%) among the offspring of affected women. The range and suitability of reproductive choices for prospective mothers is a complex area of mitochondrial medicine that needs to be managed by experienced healthcare professionals as part of a multidisciplinary team. Genetic counselling is facilitated by the identification of the underlying causative genetic defect. To provide more precise genetic counselling, further research is needed to clarify the secondary factors that account for the variable penetrance and the often marked differential expressivity of pathogenic mtDNA mutations both within and between families.

Genetic Counselling for Maternally Inherited Mitochondrial Disorders

mtDNA is a multicopy genome. When mutations exist, they can affect a varying proportion of the mtDNA present within every cell (heteroplasmy). Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency seen during transmission from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be revealed. Several questions remain, including the role of selection for and against specific alleles, whether all bottlenecks are the same, and precisely how the bottleneck is controlled during development. Although originally thought to be limited to the germline, there is evidence that bottlenecks exist in other cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. Moreover, tissue-specific bottlenecks may occur throughout life in response to environmental influences, adding further complexity to the situation. Here we review key recent findings, and suggest ways forward that will hopefully advance our understanding of the role of mtDNA in human disease.

The mitochondrial DNA genetic bottleneck: inheritance and beyond.

Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.

/pdf/modulating-mitophagy-in-mitochondrial-disease-16hsg6sm0w.pdf

Modulating mitophagy in mitochondrial disease

243rd ENMC international workshop: Developing guidelines for management of reproductive options for families with maternally inherited mtDNA disease, Amsterdam, the Netherlands, 22–24 March 2019

Modulating mitochondrial quality control in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children

Dysregulated mitophagy and mitochondrial transport in severe dominant optic atrophy due to OPA1 mutations

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Modulating mitochondrial quality control in disease transmission: towards enabling mitochondrial DNA disease carriers to have healthy children

Dysregulated mitophagy and mitochondrial transport in severe dominant optic atrophy due to OPA1 mutations