# Feasibility of Xenogeneic Mitochondrial Transplantation in Neuronal Systems: An Exploratory Study

## TL;DR

This study explores whether mitochondria from rats can be transplanted into mouse neurons, showing that it's possible and has dose-dependent effects.

## Contribution

The study demonstrates the feasibility of xenogeneic mitochondrial transplantation in neuronal systems and identifies potential uptake mechanisms.

## Key findings

- Rat mitochondria were successfully taken up by mouse neurons in a dose-dependent manner.
- Rat mitochondrial DNA was detected in mouse brains after transplantation.
- Uptake involved actin-dependent macropinocytosis and cholesterol-sensitive pathways.

## Abstract

Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post–xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability.