Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy.

Abstract

There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Earlier studies show that epithelial mitochondrial dysfunction is critical in asthma pathogenesis. Here we show for the first time that Miro1, a mitochondrial Rho-GTPase, regulates intercellular mitochondrial movement from mesenchymal stem cells (MSC) to epithelial cells (EC). We demonstrate that overexpression of Miro1 in MSC (MSCmiro(Hi)) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown (MSCmiro(Lo)) leads to loss of efficacy. Treatment with MSCmiro(Hi) was associated with greater therapeutic efficacy, when compared to control MSC, in mouse models of rotenone (Rot) induced airway injury and allergic airway inflammation (AAI). Notably, airway hyperresponsiveness and remodeling were reversed by MSCmiro(Hi) in three separate allergen-induced asthma models. In a human in vitro system, MSCmiro(Hi) reversed mitochondrial dysfunction in bronchial epithelial cells treated with pro-inflammatory supernatant of IL-13-induced macrophages. Anti-inflammatory MSC products like NO, TGF-β, IL-10 and PGE2, were unchanged by Miro1 overexpression, excluding non-specific paracrine effects. In summary, Miro1 overexpression leads to increased stem cell repair.

• Authors: Tanveer Ahmad, Shravani Mukherjee, Bijay Pattnaik, Manish Kumar, Suchita Singh, Manish Kumar, Rakhshinda Rehman, Brijendra K Tiwari, Kumar A Jha, Amruta P Barhanpurkar, Mohan R Wani, Soumya S Roy, Ulaganathan Mabalirajan, Balaram Ghosh, Anurag Agrawal
• Journal: The EMBO journal (EMBO J) Vol. 33 Issue 9 Pg. 994-1010 (May 02 2014) ISSN: 1460-2075 [Electronic] England
• PMID: 24431222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Miro-1 protein, mouse
• rho GTP-Binding Proteins

Topics

• Animals
• Biological Transport (genetics)
• Cells, Cultured
• Genetic Therapy (methods)
• Humans
• Lung (pathology)
• Lung Injury (pathology, therapy)
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism, physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Mitochondria (metabolism, transplantation)
• NIH 3T3 Cells
• Nanotubes
• Treatment Outcome
• rho GTP-Binding Proteins (genetics, physiology)