Abstract
Wharton's jelly mesenchymal stem cells (WJMSCs) transfer healthy mitochondria to cells harboring a mitochondrial DNA (mtDNA) defect. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major subgroups of mitochondrial diseases, caused by the mt.3243A>G point mutation in the mitochondrial tRNALeu(UUR) gene. The specific aim of the study is to investigate whether WJMSCs exert therapeutic effect for mitochondrial dysfunction in cells of MELAS patient through donating healthy mitochondria. We herein demonstrate that WJMSCs transfer healthy mitochondria into rotenone-stressed fibroblasts of a MELAS patient, thereby eliminating mutation burden and rescuing mitochondrial functions. In the coculture system in vitro study, WJMSCs transferred healthy mitochondria to rotenone-stressed MELAS fibroblasts. By inhibiting actin polymerization to block tunneling nanotubes (TNTs), the WJMSC-conducted mitochondrial transfer was abrogated. After mitochondrial transfer, the mt.3243A>G mutation burden of MELAS fibroblasts was reduced to an undetectable level, with long-term retention. Sequencing results confirmed that the transferred mitochondria were donated from WJMSCs. Furthermore, mitochondrial transfer of WJMSCs to MELAS fibroblasts improves mitochondrial functions and cellular performance, including protein translation of respiratory complexes, ROS overexpression, mitochondrial membrane potential, mitochondrial morphology and bioenergetics, cell proliferation, mitochondrion-dependent viability, and apoptotic resistance. This study demonstrates that WJMSCs exert bioenergetic therapeutic effects through mitochondrial transfer. This finding paves the way for the development of innovative treatments for MELAS and other mitochondrial diseases.
Highlights
Mitochondria are organelles responsible for the production of ATP, the major energy currency of the cell
Our team has previously found that umbilical cord-derived Wharton’s jelly mesenchymal stem cells (WJMSCs) yield mitochondrial transfer to Mitochondrial DNA (mtDNA)-devoid ρ0 cells and completely restore mtDNA content [21]
Mitochondrial bioenergetics, metabolic phenotype, proliferation rate, and mitochondrion-dependent viability of MELAS fibroblasts are significantly improved, to the extent they are comparable with normal fibroblasts
Summary
Mitochondria are organelles responsible for the production of ATP, the major energy currency of the cell. Mitochondrial dysfunction results in metabolic imbalance, intracellular ATP deficiency, reactive oxygen species (ROS) production, and perturbation in cell death singling [1, 2]. Mitochondrial DNA (mtDNA) is an approximately 16.6 kilobase, double-stranded, circular molecule encoding 37 genes, with several thousand copies per cell in humans [3]. Mutations in mtDNA may cause a broad spectrum of multisystemic diseases. Many patients of mitochondrial diseases harbor both normal and mutant mtDNA in a single cell, a state known as heteroplasmy. The degree of heteroplasmy and distribution of mutant mtDNA in the patient’s tissues determine the severity and phenotypic heterogeneity of the disease [4]
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