Alternative Methods for Mitochondrial Transplantation: Efficiency of Unpackaged and Lipid-Packaged Preparations (original) (raw)
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Challenges in Promoting Mitochondrial Transplantation Therapy
International Journal of Molecular Sciences
Mitochondrial transplantation therapy is an innovative strategy for the treatment of mitochondrial dysfunction. The approach has been reported to be useful in the treatment of cardiac ischemic reperfusion injuries in human clinical trials and has also been shown to be useful in animal studies as a method for treating mitochondrial dysfunction in various tissues, including the heart, liver, lungs, and brain. On the other hand, there is no methodology for using preserved mitochondria. Research into the pharmaceutical formulation of mitochondria to promote mitochondrial transplantation therapy as the next step in treating many patients is urgently needed. In this review, we overview previous studies on the therapeutic effects of mitochondrial transplantation. We also discuss studies related to immune responses that occur during mitochondrial transplantation and methods for preserving mitochondria, which are key to their stability as medicines. Finally, we describe research related to m...
Mitochondria transplantation between living cells
2021
Mitochondria and the complex endomembrane system are hallmarks of eukaryotic cells. To date, it has been difficult to manipulate organelle structures within single live cells. We developed a FluidFM-based approach to extract, inject and transplant organelles from and into living cells with subcellular spatial resolution. The approach enabled the transfer of controlled quantities of mitochondria into cells while maintaining their viability and monitoring their fate in new host cells. Transplantation of healthy and drug-impaired mitochondria into primary keratinocytes allowed real-time tracking of mitochondrial subpopulation rescue. Fusion with the mitochondrial network of recipient cells occurred 20 min after transplantation and continued for over 16 hours. After transfer of mitochondria and cell propagation over generations, we show that donor mtDNA was replicated in recipient cells without the need for selection pressure. The approach opens new prospects for the study of organelle ...
Mitochondrion, 2007
Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic approaches were initiated in the late 1980s to clarify the gene responsible for various mitochondrial diseases, and information concerning genetic mutations is currently used in the diagnosis of mitochondrial diseases. Moreover, it was also revealed that mitochondria play a central role in apoptosis, or programmed cell death, which is closely related to the loss of physiological functions of tissues. Therefore, drug therapies targeted to the mitochondria would be highly desirable. In spite of the huge amount of mechanism-based studies of mitochondrial diseases, effective therapies have not yet been established mainly because of the lack of an adequate delivery system. To date, numerous investigators have attempted to establish a mitochondrial drug delivery system. However, many problems remain to be overcome before a clinical application can be achieved. To fulfill a drug delivery targeted to mitochondria, we first need to establish a method to encapsulate various drugs, proteins, peptides, and genes into a drug carrier depending on their physical characteristics. Second, we need to target it to a specific cell. Finally, multi-processes of intracellular trafficking should be sophisticatedly regulated so as to release a drug carrier from the endosome to the cytosol, and thereafter to deliver to the mitochondria. In this review, we describe the current state of the development of mitochondrial drug delivery systems, and discuss the advantage and disadvantage of each system. Our current efforts to develop an efficient method for the packaging of macromolecules and regulating intracellular trafficking are also summarized. Furthermore, novel concept of "Regulation of intramitochondrial trafficking" is proposed herein as a future challenge to the development of a mitochondrial drug delivery system.
Mitochondrial transfer between cells: Methodological constraints in cell culture and animal models
Analytical Biochemistry, 2018
Interest in the recently discovered phenomenon of mitochondrial transfer between mammalian cells has gained momentum since it was first described in cell culture systems more than a decade ago. Mitochondria-targeting fluorescent dyes have been repurposed and are now widely used in these studies and in acute disease models, sometimes without due consideration of their limitations, while vectors containing mitochondrially-imported fluorescent proteins have complemented the use of mitochondria-targeting dyes. Genetic approaches that use mitochondrial DNA polymorphisms have also been used in some in vitro studies and in tumor models and are particularly useful where mtDNA is damaged or deleted. These approaches can also be used to study the long-term consequences of mitochondrial transfer such as in bone marrow and organ transplantation and in tumour biology where inherent mitochondrial damage is often a key feature. As research on intercellular mitochondrial transfer moves from cell culture into animal models and human diseases it will be important to understand the limitations of the various techniques in order to apply appropriate methodologies to address physiological and pathophysiological conditions.
Mitochondrial Transplantation: A Critical Analysis
Biochemistry (Moscow), 2020
BACKGROUND This story began back in 2009, when the first work on the therapeutic effect of introducing isolated mitochon dria into a rabbit's ischemic heart was published [1]. That work was carried out in the highly respected Beth Israel Deaconess Medical Center that is affiliated with Harvard Medical School under the leadership of Dr. James D. McCully. This researcher had by then more than 25 years of experience in molecular cardiology research (
Characteristics of Mitochondrial Transformation into Human Cells
Scientific Reports, 2016
Mitochondria can be incorporated into mammalian cells by simple co-incubation of isolated mitochondria with cells, without the need of transfection reagents or any other type of intervention. This phenomenon was termed mitochondrial transformation and although it was discovered in 1982, currently little is known regarding its mechanism(s). Here we demonstrate that mitochondria can be transformed into recipient cells very quickly and co-localize with endogenous mitochondria. The isolated mitochondria interact directly with cells, which engulf the mitochondria with cellular extensions in a way, which may suggest the involvement of macropinocytosis or macropinocytosis-like mechanisms in mitochondrial transformation. Indeed, macropinocytosis inhibitors but not clathrin-mediated endocytosis inhibition-treatments, blocks mitochondria transformation. The integrity of the mitochondrial outer membrane and its proteins is essential for the transformation of the mitochondria into cells; cells ...
Current progress of mitochondrial transplantation that promotes neuronal regeneration
Translational Neurodegeneration
Background: Mitochondria are the major source of intracellular adenosine triphosphate (ATP) and play an essential role in a plethora of physiological functions, including the regulation of metabolism and the maintenance of cellular homeostasis. Mutations of mitochondrial DNA, proteins and impaired mitochondrial function have been implicated in the neurodegenerative diseases, stroke and injury of the central nervous system (CNS). The dynamic feature of mitochondrial fusion, fission, trafficking and turnover have also been documented in these diseases. Perspectives: A major bottleneck of traditional approach to correct mitochondria-related disorders is the difficulty of drugs or gene targeting agents to arrive at specific sub-compartments of mitochondria. Moreover, the diverse nature of mitochondrial mutations among patients makes it impossible to develop one drug for one disease. To this end, mitochondrial transplantation presents a new paradigm of therapeutic intervention that benefits neuronal survival and regeneration for neurodegenerative diseases, stroke, and CNS injury. Supplement of healthy mitochondria to damaged neurons has been reported to promote neuronal viability, activity and neurite re-growth. In this review, we provide an overview of the recent advance and development on mitochondrial therapy. Conclusion: Key parameters for the success of mitochondrial transplantation depend on the source and quality of isolated mitochondria, delivery protocol, and cellular uptake of supplemented mitochondria. To expedite clinical application of the mitochondrial transplantation, current isolation protocol needs optimization to obtain high percentage of functional mitochondria, isolated mitochondria may be packaged by biomaterials for successful delivery to brain allowing for efficient neuronal uptake.
Artificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications
Stem cells international, 2017
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, ...