RRC ID 78200
Author Liu L, Yang J, Otani Y, Shiga T, Yamaguchi A, Oda Y, Hattori M, Goto T, Ishibashi S, Kawashima-Sonoyama Y, Ishihara T, Matsuzaki Y, Akamatsu W, Fujitani M, Taketani T.
Title MELAS-Derived Neurons Functionally Improve by Mitochondrial Transfer from Highly Purified Mesenchymal Stem Cells (REC).
Journal Int J Mol Sci
Abstract Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome, caused by a single base substitution in mitochondrial DNA (m.3243A>G), is one of the most common maternally inherited mitochondrial diseases accompanied by neuronal damage due to defects in the oxidative phosphorylation system. There is no established treatment. Our previous study reported a superior restoration of mitochondrial function and bioenergetics in mitochondria-deficient cells using highly purified mesenchymal stem cells (RECs). However, whether such exogenous mitochondrial donation occurs in mitochondrial disease models and whether it plays a role in the recovery of pathological neuronal functions is unknown. Here, utilizing induced pluripotent stem cells (iPSC), we differentiated neurons with impaired mitochondrial function from patients with MELAS. MELAS neurons and RECs/mesenchymal stem cells (MSCs) were cultured under contact or non-contact conditions. Both RECs and MSCs can donate mitochondria to MELAS neurons, but RECs are more excellent than MSCs for mitochondrial transfer in both systems. In addition, REC-mediated mitochondrial transfer significantly restored mitochondrial function, including mitochondrial membrane potential, ATP/ROS production, intracellular calcium storage, and oxygen consumption rate. Moreover, mitochondrial function was maintained for at least three weeks. Thus, REC-donated exogenous mitochondria might offer a potential therapeutic strategy for treating neurological dysfunction in MELAS.
Volume 24(24)
Published 2023-12-6
DOI 10.3390/ijms242417186
PII ijms242417186
PMID 38139018
PMC PMC10742994
MeSH Acidosis, Lactic* / metabolism Acidosis, Lactic* / pathology DNA, Mitochondrial / metabolism Humans MELAS Syndrome* / genetics MELAS Syndrome* / therapy Mesenchymal Stem Cells* / metabolism Mitochondria / genetics Mitochondrial Diseases* / metabolism Neurons / pathology
Human and Animal Cells 201B7(HPS0063) HPS0070 HPS0458 HPS0461 HPS2864