Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Mitochondria: emerging therapeutic strategies for oocyte rescue.

As the vital organelles for cell energy metabolism, mitochondria are essential for oocyte maturation, fertilization, and embryo development. Abnormalities in quantity, quality, and function of mitochondria are closely related to poor fertility and disorders, such as decreased ovarian reserve (DOR), premature ovarian aging (POA), and ovarian aging, as well as maternal mitochondrial genetic disease caused by mitochondrial DNA (mtDNA) mutations or deletions. Mitochondria have begun to become a therapeutic target for infertility caused by factors such as poor oocyte quality, oocyte aging, and maternal mitochondrial genetic diseases. Mitochondrial replacement therapy (MRT) has attempted to use heterologous or autologous mitochondria to rebuild healthy state of oocyte by increasing the amount of mitochondria (e.g., partial ooplasm transfer, autologous mitochondrial transfer), or to stop the transmission of mtDNA diseases by replacing abnormal maternal mitochondria (e.g., pronuclei transfer, spindle transfer, polar body transfer). Among them, autologous mitochondrial transfer is the most promising therapeutic technology as of today which does not involve using a third party, but its clinical efficacy is controversial due to many factors such as the aging phenomenon of germ line cells, the authenticity of the existence of ovarian stem cells (OSC), and secondary damage caused by invasive surgery to patients with poor ovarian function. Therefore, the research of optimal autologous cell type that can be applied in autologous mitochondrial transfer is an area worthy of further exploration. Besides, the quality of germ cells can also be probably improved by the use of compounds that enhance mitochondrial activity (e.g., coenzyme Q10, resveratrol, melatonin), or by innovative gene editing technologies which have shown capability in reducing the risk of mtDNA diseases (e.g., CRISPR/Cas9, TALENTs). Though the current evidences from animal and clinical trials are not sufficient, and some solutions of technical problems are still needed, we believe this review will guide a new direction in the possible clinical applied mitochondrial-related therapeutic strategies in reproductive medicine.

A conception of genetic parenthood.

We seek to develop a plausible conception of genetic parenthood, taking a recent discussion by Heidi Mertes as our point of departure. Mertes considers two conceptions of genetic parenthood-one invoking genetic resemblance and the other genetic inheritance-and presents counter-examples to both conceptions. We revise Mertes' second conception so as to avoid these and related counter-examples.

Algunas consideraciones sobre la transferencia mitocondrial: ¿un nuevo problema para la bioética? / Some thoughts on the mitochondrial transfer: a new issue for bioethics? / Algumas considerações sobre a transferência mitocondrial: um novo problema para a bioética?

En febrero de 2015 el Reino Unido dio el primer paso para la aprobación de la transferencia mitocondrial como técnica terapéutica. Teóricamente, gracias a eso será posible para muchas mujeres engendrar descendencia libre de patologías asociadas a defectos mitocondriales. Sin embargo, esta práctica enfrenta severas dudas desde un punto de vista ético. Entre las objeciones destacan: su estrecha vinculación con la clonación humana; la alteración de los genes de la línea germinal; la modificación de la identidad del ser humano al que dará lugar; la destrucción de embriones humanos que envuelve, o el elevado riesgo que encierra para la salud del ser humano resultante. En este texto se analiza la solvencia de todas estas objeciones de forma crítica, resaltando las fortalezas de algunas de ellas. En particular, se aboga por una restricción cuidadosa del uso de esta técnica, que promueva el empleo de alternativas más respetuosas con la salud del futuro ser humano.

In February 2015 the United Kingdom took the first step towards the adoption of mitochondrial transfer as a therapeutic technique. Theoretically, it will make it possible for many women to get rid of pathologies associated with mitochondrial defects. However, this practice has been subjected to severe doubts from an ethical standpoint. Among these objections, we could highlight the following: its close association with human cloning; the alteration of the germline genes; the modification in the identity of the human being involved; the destruction of human embryos; or the high risk to the health of the human being. In this text we will analyze these objections critically, highlighting the strength of all of them. As a result, we will call for a careful restriction of the use of this technique, and the promotion of the use of alternative options much more respectful of the human future.

Em fevereiro de 2015 o Reino Unido deu o primeiro passo para a aprovação da transferência mitocondrial como técnica terapêutica. Teoricamente, graças a isso será possível a muitas mulheres engendrar descendência livre de patologias associadas a defeitos mitocondriais. No entanto, esta prática enfrenta severas dúvidas a partir de um ponto de vista ético. Entre as objeções destacam: sua estreita vinculação com a clonagem humana; a alteração dos genes da linha germinal; a modificação da identidade do ser humano ao qual dará lugar; a destruição de embriões humanos que envolve, ou o elevado risco que encerra para a saúde do ser humano resultante. Neste texto se analisa a solvência de todas estas objeções de forma crítica, ressaltando as fortalezas de algumas delas. Em particular, se advoga por uma restrição cuidadosa do uso desta técnica, que se promova o emprego de alternativas mais respeitosas com a saúde do futuro ser humano.

Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.

Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.

The advances and new technologies for the study of mitochondrial diseases / Avanços e novas tecnologias para o estudo das doenças mitocondriais

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.

RESUMO As doenças genéticas mitocondriais são responsáveis pelos erros inatos do metabolismo mais comuns, causados por mutações tanto em genes nucleares como no DNA mitocondrial. Este artigo apresenta a origem procariótica dessa organela, e a relação entre os genomas nuclear e mitocondrial, bem como modelos evolutivos correntes para esses mecanismos. Também trata da estrutura dos genes mitocondriais, seu padrão de expressão, características clínicas de defeitos genéticos, riscos de transmissão e técnicas atualmente utilizadas para evitar esses eventos em reprodução humana assistida. Finalmente, discute as implicações éticas dessas possibilidades.

Concise reviews: Assisted reproductive technologies to prevent transmission of mitochondrial DNA disease.

While the fertilized egg inherits its nuclear DNA from both parents, the mitochondrial DNA is strictly maternally inherited. Cells contain multiple copies of mtDNA, each of which encodes 37 genes, which are essential for energy production by oxidative phosphorylation. Mutations can be present in all, or only in some copies of mtDNA. If present above a certain threshold, pathogenic mtDNA mutations can cause a range of debilitating and fatal diseases. Here, we provide an update of currently available options and new techniques under development to reduce the risk of transmitting mtDNA disease from mother to child. Preimplantation genetic diagnosis (PGD), a commonly used technique to detect mutations in nuclear DNA, is currently being offered to determine the mutation load of embryos produced by women who carry mtDNA mutations. The available evidence indicates that cells removed from an eight-cell embryo are predictive of the mutation load in the entire embryo, indicating that PGD provides an effective risk reduction strategy for women who produce embryos with low mutation loads. For those who do not, research is now focused on meiotic nuclear transplantation techniques to uncouple the inheritance of nuclear and mtDNA. These approaches include transplantation of any one of the products or female meiosis (meiosis II spindle, or either of the polar bodies) between oocytes, or the transplantation of pronuclei between fertilized eggs. In all cases, the transferred genetic material arises from a normal meiosis and should therefore, not be confused with cloning. The scientific progress and associated regulatory issues are discussed.