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

Abstract

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.

Figure 1

Natural mitochondria transfer. Viable and nonfunctional mitochondria can be shared by the cell inducing different cellular responses from cellular rescue to promoting inflammation. The first transfer mechanism is the microvesicle transport of mitochondria, it has been observed specially in MSCs in which the secreted microvesicles carrying mitochondria, once internalized by the recipient cells, induce its rescue from cellular damage and enhance the phagocytic properties of immune cells [182, 183]. The second way of transfer is by TNTs; many cells share the ability to produce them and transport mitochondria with proven effects in the rescue from cellular damage, metabolic reprogramming, and immune enhancement and it was also associated with its differentiation [65, 184]. During cellular stress, defective mitochondria can be released without being covered like in apoptotic or mitoapoptotic bodies and being naked promoting the immune response and inflammation [17, 77, 185].

Figure 2

Artificial mitochondria transfer (AMT) and transplant. Different techniques emerged to mimic the natural transfer or mitochondria on its in vivo and in vitro applications. The coincubation technique was the first proposed in which the antibiotic resistance carried in the mitochondrial DNA was passed to sensitive cells [9], later after the technique was used to rescue respiratory deficient cells among other damaged cells [10, 11, 14, 63]. Microinjection of exogenous mitochondria was applied in assays to eliminate the endogenous copies of oocytes carrying mitochondrial diseases [90, 93]. The photothermal nanoblade effectively transferred isolated mitochondria inside the cell; even if they showed great effectiveness, its application is limited to small cell numbers [12]. Two different approaches were developed to facilitate the mitochondria internalization in the recipient cells, the first is by using Pep-1 and the other with magnetic beads (Magnetomitotransfer) designed to bind to TOM22 a receptor complex in the mitochondrial membrane. The MitoCeption technique uses a thermic shock and a centrifugation to improve the process of mitochondria uptake; first applied in cancer cells, this technique induces the metabolic reprogramming of these cells. The in vivo application of the mitochondria transfer applies two approaches: the first is to directly inject mitochondria to the harmed tissue and the other in the circulatory system close to the area of interest. Both of them have shown to restore tissue function but the in situ injection showed better results [16, 49, 50].