Mitochondrial Transplantation: Adaptive Bio-enhancement

Corresponding Author:

Xiaobo Lu
Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
E-mail: fylxmgg@gmail.com

Received: 12-Sept-2024, Manuscript No. fmci-24-148712;
Editor assigned: 14-Sept-2024, PreQC No. fmci-24-148712(PQ);
Reviewed: 20-Sept-2024, QC No. fmci-24-148712(Q);
Revised: 23-Sept-2024, Manuscript No. fmci-24-148712(R);
Published: 29-Sept-2024

Abstract

 Mitochondria, known as the powerhouse of the cell, are essential for cellular energy production. Dysfunction in mitochondrial function can significantly affect various organs. Transplanting healthy mitochondria can enhance the bioenergetics of diseased cells and treat various conditions, yet the limits of mitochondrial transplantation are still unknown. Our study reveals that the source of transplanted mitochondria is not restricted by species, and recipient cells show no significant immune response to mitochondria from different lineages. We also found that metabolic compatibility between the recipient and exogenous mitochondria is crucial, and transplanting mitochondria from different species can endow recipient cells with distinct characteristics to combat diseases. Furthermore, our data indicate that there is competition among mitochondria with varying functions, with more powerful mitochondria yielding better therapeutic effects. Notably, we have not yet found an upper limit for the bio-enhancement provided by exogenous mitochondria. Our research proposes a feasible path for human bio-enhancement through mitochondrial transplantation-adaptive bio-enhancement.

Keywords

Mitochondrial transplantation • Immune response • Metabolic compatibility • Competition • Bio-enhancement

Introduction

Mitochondrial transplantation involves isolating mitochondria from normal cells or tissues and transferring them to diseased areas either directly or indirectly to improve the function of damaged cells, thereby aiding in treatment. Compared to organ, tissue, or cell transplantation, mitochondrial transplantation is a novel and milder alternative therapy. In 2009, Boston Children 's Hospital first reported mitochondrial transplantation, injecting mitochondria into ischemic regions of the rabbit heart and observing significant therapeutic effects [1]. To date, mitochondrial transplantation has shown promising therapeutic outcomes in various organ and tissue injuries, including the heart, brain, spinal cord, lungs, kidneys, liver, skeletal muscle, and skin, as well as in conditions such as sepsis and cancer [2-12].

Despite the proven safety and therapeutic efficacy of mitochondrial transplantation in numerous diseases, its full potential remains unclear [13]. Transplanting functionally normal mitochondria to restore the function of dysfunctional mitochondria in diseased cells involves differences in mitochondrial function, which enhances the function of diseased cells. Preemptively providing normal cells with exogenous mitochondria can grant them a higher damage threshold, thereby bioenergetically enhancing normal cells [3,14]. The question arises: can we select mitochondria with different characteristics for different disease populations or use mitochondria with functions superior to normal mitochondria as a purely adaptive bioenhancement strategy? This is a topic worth exploring.

In this study, we expanded the sources of mitochondria for transplantation and demonstrated the universality of mitochondrial transplantation. We further utilized the lineagespecific characteristics of mitochondria to treat cells under different disease conditions, highlighting the importance of metabolic matching. Additionally, we obtained hybrid mitochondria with enhanced therapeutic suitability by inducing cell fusion to combine multiple lineage characteristics. Building on this, we discovered that mitochondria with greater functional potency exhibited an overwhelmingly superior therapeutic effect compared to their lineagespecific counterparts, even enhancing the function of normal cells to some extent. Similar results were observed in animal experiments, suggesting that mitochondrial transplantation could potentially be used as a means of biological enhancement. This significantly broadens the therapeutic value of mitochondrial transplantation and offers a new research direction for biological augmentation.

■Universality of mitochondrial transplantation

Mitochondria, a fundamental and essential organelle present in most eukaryotic cells, have a relatively simple genome structure, typically ranging in size from 15 kb to 60 kb. Their primary function is to supply energy to cells [15,16]. The prevailing theory suggests that mitochondria originated from α-proteobacteria that established a stable endosymbiotic relationship with the host during the process of organelle formation. As the αproteobacteria progressively reduced their protein repertoire and transferred most of their genetic material to the host nucleus, this unique evolutionary process likely explains why mitochondria, even when transplanted between different species or across species, do not elicit significant immune or inflammatory responses [15,17-19]. Current research on mitochondrial transplantation primarily uses mitochondria from three sources: various cell lines, human umbilical cord mesenchymal stem cells, and tissues such as liver, skeletal muscle,, brain, and platelets, with the experimental animals mainly being humans, rabbits, mice, pigs, and rats [1,20-33]. We aimed to expand the species origin of mitochondria used for transplantation to enhance the therapeutic potential of this approach.

Using green fluorescent markers, we labeled mitochondria from 13 different animal species, including African Green Monkey Kidney Cells (Vero), Bovine Kidney Cells (MDCK), MDBK Canine Kidney Cells (MDBK), Feline Kidney Cells (CRFK), Porcine Kidney Cells (PK15), Chicken Hepatocarcinoma Cells (LMH), Spodoptera Frugiperda Cells (SF9), turtle liver tissue, bullfrog liver tissue, quail liver tissue, lizard liver tissue, large yellow croaker liver tissue, and eel liver tissue. Through ATP assays, JC-1 staining, transmission electron microscopy, and mitochondrial respiratory chain complex activity assays, we confirmed that the isolated mitochondria from these species were biofunctionally intact and structurally well-preserved (Figures 1A-1G) . We then co-cultured Mito-Tracker Green-labeled mitochondria from these species with WGA594 red fluorescently-labeled Human Cardiomyocytes (AC16), Human Hepatocarcinoma Cells (HepG2), and Mouse Skin Fibroblasts (L929), observing efficient internalization and significant co-localization of the various mitochondria within recipient cells (Figure 1H).

To evaluate the safety of these interspecies mitochondrial transplants, we collected the supernatants of the co-cultured cells and assessed immune and inflammatory responses using ELISA. We found no significant changes in the levels of IL-6, IL-10, and TNF-α in the mitochondria-transplanted groups compared to normal cells, indicating a high degree of safety for multi-species mitochondrial transplantation (Figures 1I-1N).

Additionally, we included mitochondria from Vaucheria litorea, further pushing the species boundary. After labeling these mitochondria with Mito-Tracker Red and co-culturing them with WGA594-labeled L929 cells, we observed that although most of the plant mitochondria were damaged due to extraction techniques, some intact ones were still internalized by the cells (Figures 1A and 1B). Given the complexity of plant mitochondrial extraction and the significant genetic divergence between plant and animal mitochondria, the safety and efficacy of such transplants would substantially bolster our findings. We conducted Vaucheria litorea mitochondrial transplantation every three days for 25 days, initially observing immune responses in the first five transplants. However, starting from the sixth transplant, due to contamination and other factors, IL-6, IL-10, and TNF-α levels surged, leading to cell death (Figures 1C-1F). While the outcome of plant mitochondrial transplantation is largely acceptable, as the extraction of plant mitochondria has a high contamination risk, the initial success of these transplants sufficiently demonstrated the universality and safety of mitochondrial transplantation. The internalization of mitochondria from multiple species reflects the cellular "inclusiveness" to various foreign organelles.

■Outcomes

• A: Analysis of membrane potential in both cells and animals isolated mitochondria. Ctrl: Mitochondria subjected to two freeze-thaw cycles at -80°C and 37°C to completely disrupt their structure and function, used for comparison.

• B: ATP production capacity in both cells and animals isolated mitochondria. Ctrl: Mitochondria subjected to two freezethaw cycles at -80°C and 37°C, used for comparison.