Polymer Functionalization of Isolated Mitochondria for Cellular Transplantation and Metabolic Phenotype Alteration

Abstract

Aberrant mitochondrial energy transfer underlies prevalent chronic health conditions, including cancer, cardiovascular, and neurodegenerative diseases. Mitochondrial transplantation represents an innovative strategy aimed at restoring favorable metabolic phenotypes in cells with dysfunctional energy metabolism. While promising, significant barriers to in vivo translation of this approach abound, including limited cellular uptake and recognition of mitochondria as foreign. The objective is to functionalize isolated mitochondria with a biocompatible polymer to enhance cellular transplantation and eventual in vivo applications. Herein, it is demonstrated that grafting of a polymer conjugate composed of dextran with triphenylphosphonium onto isolated mitochondria protects the organelles and facilitates cellular internalization compared with uncoated mitochondria. Importantly, mitochondrial transplantation into cancer and cardiovascular cells has profound effects on respiration, mediating a shift toward improved oxidative phosphorylation, and reduced glycolysis. These findings represent the first demonstration of polymer functionalization of isolated mitochondria, highlighting a viable strategy for enabling clinical applications of mitochondrial transplantation.

Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies

“…The authors showed significant enhancement of the survival of dopaminergic neurons and support of mitochondrial function after mitochondria were injected into a mouse model of Parkinson’s disease ( Chang et al, 2016 ). More recently, biocompatible polymers (dextran with lipophilic cation triphenylphosphonium) have been suggested as a more effective strategy of coating of isolated mitochondria to improve uptake ( Wu et al, 2018 ).…”

Design, Synthesis, Investigation, and Application of a Macromolecule Photoswitch

“…Furthermore, research also focuses on the functionalization of macromolecules (Tseng et al, 2016; Cao et al, 2018; Wu et al, 2018). Although methods for macromolecule modification are numerous, a flexible, moderate, and a reliable reaction is still an effective and efficient method of polymer modification.…”

Intercellular mitochondrial transfer as a means of tissue revitalization

“… 173 Some progress has been made to enhance the efficacy of the transfer of isolated mitochondria into recipient cells. 174 , 175 Maeda et al 175 innovatively combined mitochondria with the transactivator of transcription (TAT) peptide of human immunodeficiency virus and dextran, which greatly enhanced the cellular incorporation of isolated mitochondria and improved the rescue effect of mitochondrial replenishment in damaged CMs. In the TAT–dextran complex, the TAT peptide facilitates the engulfment of mitochondria by recipient cells, and dextran stabilizes the combination with the outer mitochondrial membrane.…”