bims-mitrat 2025-02-09 papers

Ann Surg. 2025 Feb 06.

Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury.

Avinash Naraiah Mukkala, Bruna Araujo David, Menachem Ailenberg, Jady Liang, Chirag Manoj Vaswani, Danielle Karakas, Rachel Goldfarb, William Barbour, Avishai Gasner, Ruoxian Scarlet Wu, Raluca Petrut, Mirjana Jerkic, Ana C Andreazza, Claudia Dos Santos, Heyu Ni, Haibo Zhang, Andras Kapus, Paul Kubes, Ori David Rotstein.

OBJECTIVE: To investigate the hepatoprotective effects of mitochondrial transplantation in a murine liver ischemia/reperfusion (I/R) model.
SUMMARY BACKGROUND DATA: Sequential liver ischemia followed by reperfusion (I/R) is a pathophysiological process underlying hepatocellular injury in a number of clinical contexts, such as hemorrhagic shock/resuscitation, major elective liver surgery and organ transplantation. A unifying pathogenic consequence of I/R is mitochondrial dysfunction. Restoration of mitochondria via transplantation (MTx) has emerged as potential therapeutic in I/R. However, its role in liver I/R and its mechanisms of action remain poorly defined.
METHODS: We investigated the hepatoprotective effects of MTx in an in vivo mouse model of liver I/R and used in vivo imaging and various knockout and transgenic mouse models to determine the mechanism of protection.
RESULTS: We found that I/R-induced hepatocellular injury was prevented by MTx, as measured by plasma ALT, AST and liver histology. Additionally, I/R-induced pro-inflammatory cytokine release (IL-6, TNFα) was dampened by MTx, and anti-inflammatory IL-10 was enhanced. Moreover, MTx lowered neutrophil infiltration into both the liver sinusoids and lung BALF, suggesting a local and distant reduction in inflammation. Using in vivo intravital imaging, we found that I/R-subjected Kupffer cells (KCs), rapidly sequestered transplanted mitochondria, and acidified mitochondria within lysosomal compartments. To specifically interrogate the role of KCs, we depleted KCs using the diphtheria toxin-inducible Clec4f/iDTR transgenic mouse, then induced I/R, and discovered that KCs are necessary for the beneficial effects of MTx. Finally, we induced I/R in complement receptor of the immunoglobulin superfamily (CRIg) knockout mice and found that CRIg was required for mitochondria capture by KCs and mitochondrial-mediated hepatoprotection.
CONCLUSIONS: In this study, we demonstrated that CRIg-dependent capture of mitochondria by I/R-subjected Kupffer cells is a hepatoprotective mechanism in vivo. These data progress knowledge on the mechanisms of MTx and opens new avenues for clinical translation.

DOI: https://doi.org/10.1097/SLA.0000000000006655

J Biomed Mater Res B Appl Biomater. 2025 Feb;113(2): e35537

Physicochemical Characterization of Hyaluronic Acid-Methylcellulose Semi-Gels for Mitochondria Transplantation.

A Jamie Ahmed, Zoe A Gallegos, Md Abu Monsur Dinar, Patrick G Sullivan, Jason E DeRouchey, Samir P Patel, Alexander G Rabchevsky, Thomas D Dziubla.

Traumatic spinal cord injury (SCI) presents a significant medical challenge due to its intricate nature and treatment complexities. SCI can cause physical impairments by affecting neural and motor functions as well as initiating a series of pathophysiological events exacerbating the initial trauma. Leakage from ruptured neurons and vessels disrupt ionic balance and induces excitotoxicity, leading to progressive cellular degeneration. Introducing mitochondria to the SCI lesion has shown potential in attenuating secondary injury. Mitochondria transplantation improves cellular bioenergetics and reduces concentration of reactive oxygen species achieving homeostasis and neuroprotection. Nonetheless, keeping mitochondria viable outside cell environment for a time longer than a few minutes proves to be challenging. Additionally, localized delivery to the injury site has also been limited by other factors including flow rate of cerebrospinal fluid that washes away mobilized organelle from the compromised tissue site. Previously we showed that using hyaluronic acid-methylcellulose semi-gels (HAMC) as a biocompatible, erodible thermogelling delivery vehicle helped to overcome some of these challenges. HAMC allows for controlled release at and around the injury site, utilizing the reverse thermogelling property of MC. Sustained release of mitochondria at slower rate can increase their uptake in spinal tissue. To better optimize the semi-gel delivery of mitochondria requires a more complete understanding of the physicochemical properties of the HAMC semi-gels. We have used ultraviolet-visible spectroscopy to measure optical density of HAMC semi-gels for different HA to MC ratios and examine the temperature dependent gelation properties above their low critical solution temperature (LCST). The viscosity and degree of crystallinity of the resulting HAMC semi-gels were also assessed. Semi-gel erosion and mitochondrial release over time were studied using a fluorescence microplate reader. Lastly, seahorse assay was used to study released mitochondria respiration and viability after incubation in HAMC semi-gel.

Keywords: bio‐erodible semi‐gels; hyaluronic acid; mitochondria transplantation; spinal cord injuries

DOI: https://doi.org/10.1002/jbm.b.35537

Ann Rheum Dis. 2025 Jan 31. pii: S0003-4967(25)00070-6. [Epub ahead of print]

Mitochondrial transplantation as a novel therapeutic approach in idiopathic inflammatory myopathy.

Jeong Yeon Kim, Young Cheol Kang, Min Jung Kim, Seon Uk Kim, Hae Rim Kang, Jeong Seon Yeo, Yujin Kim, Shin-Hye Yu, Byeongwook Song, Jung Wook Hwang, Yun-Sang Lee, Jung Woo Byun, Dae Hyun Yoo, Hyun Sook Kim, Kyuboem Han, Chun-Hyung Kim, Eun Young Lee.

OBJECTIVES: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: PN-101 transplantation could serve as a novel treatment for IIM by enhancing mitochondrial repair and reducing inflammation in muscle tissues.

DOI: https://doi.org/10.1016/j.ard.2024.11.005

Stem Cell Res Ther. 2025 Feb 07. 16(1): 54

Mitochondrial transplantation for cardioprotection and induction of angiogenesis in ischemic heart disease.

Parisa Hassanpour, Fatemeh Sadeghsoltani, Solmaz Saghebasl, Safieh Boroumand, Parisa Khanicheragh, Seyed Hossein Ahmadi Tafti, Reza Rahbarghazi, Mohammad Rahmati.

To date, the regenerative potential of mitochondrial transplantation (MT) has been extensively investigated under several pathologies. Among various cardiovascular diseases, ischemic heart disease (IHD), the most prevalent pathological condition in human medicine, is induced by coronary artery narrowing, or occlusion, leading to bulk necrotic changes and fibrosis within the myocardium. Data associated with the pro-angiogenic activity of mitochondria have not been completely elucidated in terms of cardiac tissue regeneration. Here, we aimed to highlight the recent studies and advantages related to the application of mitochondrial mass in the ischemic myocardium. How and by which mechanisms, mitochondria can reduce aberrant myocardial tissue remodeling via different pathways such as angiogenesis and de novo blood formation was discussed in detail. We hope that data from the current review article help us understand the molecular and cellular mechanisms by which transplanted mitochondria exert their regenerative properties in the ischemic myocardium.

Keywords: Angiogenesis; Cardiac tissue regeneration; Ischemic heart disease; Mitochondrial transplantation

DOI: https://doi.org/10.1186/s13287-025-04193-w