Date Published: January 03, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Suhong Wu, Aijun Zhang, Shumin Li, Somik Chatterjee, Ruogu Qi, Victor Segura‐Ibarra, Mauro Ferrari, Anisha Gupte, Elvin Blanco, Dale J. Hamilton.
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.
Efficient free energy transfer is necessary for normal cellular function. The failure to properly regulate mitochondrial bioenergetics underlies a variety of chronic diseases. As an example, high‐energy requiring cancer cells exhibit a phenotypic transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (i.e., the Warburg effect),1 a phenomenon that in turn facilitates the growth and spread of these cells.2 On the other hand, reduced phosphocreatine‐to‐adenosine triphosphate (ATP) ratios observed in failing hearts highlight the energy‐depleted nature of the organ.3 Moreover, mitochondrial dysfunction is a hallmark of neurological conditions such as Parkinson’s4 and Alzheimer’s5 disease. Thus, novel treatment strategies aimed at improving aberrant energy metabolism stand to significantly impact the management of a variety of challenging disorders.6
Herein, we developed a strategy to polymerically functionalize isolated mitochondria for purposes of transplantation into cells and tissues to alter dynamics of energy handling such as substrate selection and efficiency of electron transport. A Dextran‐TPP polymer conjugate comprehensively coated isolated mitochondria, with the coating shown to protect mitochondrial respiratory function. Our results highlight efficient internalization of dextran‐coated mitochondria into breast cancer and cardiac cell lines, with an approximate 3‐fold increase compared with uncoated mitochondria. Last, mitochondrial transplantation into both cancer and cardiac cell lines resulted in a significant shift in the bioenergetic phenotype from a glycolytic to oxidative state. Our findings represent the first demonstration of polymer functionalization of mitochondria for purposes of cellular transplantation, opening potential avenues for translation of this approach for treatment of diseases characterized by metabolic impairment. In light of our promising findings, future studies will focus on in vivo evaluation of this approach in relevant models of cancer, heart failure, and neurodegenerative disease.
The authors declare no conflict of interest.