Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 ​mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.

Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell–cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs. In this study, we tested the potential of EVs as therapeutic agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. First, we found that the mesenchymal stem-cell-derived EVs (MSC-EVs) enabled the rescue of the cytopathic effect of SARS-CoV-2 virus and the suppression of proinflammatory responses in the infected cells by inhibiting the viral replication. We found that these anti-viral responses were mediated by 17 miRNAs matching the rarely mutated, conserved 3′-untranslated regions (UTR) of the viral genome. The top five miRNAs highly expressed in the MSC-EVs, miR-92a-3p, miR-26a-5p, miR-23a-3p, miR-103a-3p, and miR-181a-5p, were tested. They were bound to the complemented sequence which led to the recovery of the cytopathic effects. These findings suggest that the MSC-EVs are a potential candidate for multiple variants of anti-SARS-CoV-2.

This study aimed to investigate the efficacy of mitochondrial transplantation as a therapeutic intervention for idiopathic inflammatory myopathy (IIM). This study used a comprehensive approach, incorporating both in vitro and in vivo IIM models, and conducted a first-in-human clinical trial to assess the effectiveness and safety of mitochondria isolated from human umbilical cord mesenchymal stem cells (PN-101). Mitochondria isolated from umbilical cord mesenchymal stem cells were designated as PN-101. The efficacy of PN-101 was assessed using myoblasts derived from patients with IIM and C2C12 mouse perforin/granzyme B-treated myoblasts as an in vitro IIM model. PN-101's effect on IIM was examined using C protein-induced myositis (CIM) mice as an in vivo model. The efficacy and safety of PN-101 were evaluated in a phase 1/2a clinical trial involving 9 adult patients with refractory polymyositis or dermatomyositis. The myoblasts derived from patients with IIM exhibited defects in mitochondrial function and myogenesis. PN-101 transplantation enhances muscle differentiation and mitochondrial function in IIM myoblasts. PN-101 also enhanced intracellular adenosine triphosphate content, cell viability, and myogenesis in C2C12 perforin/granzyme B-treated myoblasts. In an in vivo model, PN-101 reduced myositis severity by exhibiting anti-inflammatory effects and restoring the CIM-induced metabolic shift. In a phase 1/2a prospective clinical trial involving adult patients with refractory IIM, PN-101 demonstrated no severe adverse drug reactions and showed at least minimal improvement in the International Myositis Assessment and Clinical Studies Group (IMACS)-Total Improvement Scores (TISs) compared with baseline. PN-101 transplantation could serve as a novel treatment for IIM by enhancing mitochondrial repair and reducing inflammation in muscle tissues.

Shin-Hye Yu, Soomin Kim, Yujin Kim, Seo-Eun Lee, Jong Hyeok Park, Gayoung Cho, Jong-Cheon Ha, Hahnsun Jung, Sang-Min Lim, Kyuboem Han, Hong Kyu Lee, Young Cheol Kang & Chun-Hyung Kim. BMB Reports 2022;55:136-41. https://doi.org/10.5483/BMBRep.2022.55.3.083

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing in vitro using a cell-based model. Wound repairs were assessed by 2D gap closure experiment in wound scratch assay using human dermal fibroblasts (hDFs). Results demonstrated that pl-MT were successfully internalized into hDFs. It increased cell proliferation and promoted the closure of wound gap. Importantly, pl-MT suppressed both intracellular and mitochondrial ROS production induced by hydrogen peroxide, cisplatin, and TGF-β in hDFs. Taken together, these results suggest that pl-MT transfer might be used as a potential therapeutic strategy for wound repair. What is the context? What is new? What is the impact?

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MT^GFP). When MT^GFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MT^GFP injected intravenously into normal mice, MT^GFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.