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Cited by 47Mesenchymal stem cell researchMitochondrial Function and PathologyAutophagy in Disease and Therapy

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Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

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Mukkala, Avinash Naraiah, Jerkic, Mirjana, Khan, Zahra, Szaszi, Katalin, Kapus, Andras, Rotstein, Ori·2023·International Journal of Molecular Sciences
DOI 10.3390/ijms242115788PMC PMC10647450
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Abstract

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

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Crossref · 10.3390/ijms242115788

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Figures

Figure 1 MQC pathways and main regulatory molecules essential for mitochondrial function, maintenance and cell homeostasis (created with BioRender.com). Mt undergo fission and fusion, oscillating between globular and elongated morphology. Mitochondrial fission is essential for the proper distribution of Mt into the daughter cells during division and serves mitophagy by generating “edible” smaller units from injured Mt. Excessive fission is both a major sign and an inducing factor of cell stress, and is associated with deterioration of ATP production, extensive ROS generation, apoptosis, or necrotic death. The key component of mitochondrial fission is Drp1 which, upon induction of fragmentation, can translocate from the cytosol to the outer mitochondrial membrane (OMM). The opposite process, fusion, is catalyzed by the Mfn1 and Mfn2 in the OMM and OPA1 in the inner mitochondrial membrane (IMM). The maintenance of mitochondrial network integrity is orchestrated by the processes of mitophagy and mitochondrial biogenesis. Regulation of Mt biogenesis is coordinated by PGC1α, SIRT1 and AMPK, increasing the replication of MtDNA and the expression of mitochondrial proteins. The key mitophagy pathways are divided into receptor-mediated mitophagy and ubiquitin-mediated mitophagy. During receptor-mediated mitophagy, under mitochondrial stress (i.e., hypoxia or depolarization), mitophagy receptors localize to the OMM. Both major mitophagy receptors, FUNDC1 and BNIP3L/NIX, facilitate phagophore formation. Ubiquitin-dependent mitophagy is PINK1/Parkin-dependent, and phosphorylation of both Parkin and ubiquitin is conducted by PINK1. Under Mt stress, PINK1 and Parkin decorate Mt with phosphor-ubiquitin chains. Mt covered in ubiquitin are recognized by multiple autophagy receptors that assemble the autophagosomal machinery for degradation of damaged Mt. LC3 is involved in both ubiquitin-dependent and receptor-mediated mitophagy.
Figure 1 MQC pathways and main regulatory molecules essential for mitochondrial function, maintenance and cell homeostasis (created with BioRender.com). Mt undergo fission and fusion, oscillating between globular and elongated morphology. Mitochondrial fission is essential for the proper distribution of Mt into the daughter cells during division and serves mitophagy by generating “edible” smaller units from injured Mt. Excessive fission is both a major sign and an inducing factor of cell stress, and is associated with deterioration of ATP production, extensive ROS generation, apoptosis, or necrotic death. The key component of mitochondrial fission is Drp1 which, upon induction of fragmentation, can translocate from the cytosol to the outer mitochondrial membrane (OMM). The opposite process, fusion, is catalyzed by the Mfn1 and Mfn2 in the OMM and OPA1 in the inner mitochondrial membrane (IMM). The maintenance of mitochondrial network integrity is orchestrated by the processes of mitophagy and mitochondrial biogenesis. Regulation of Mt biogenesis is coordinated by PGC1α, SIRT1 and AMPK, increasing the replication of MtDNA and the expression of mitochondrial proteins. The key mitophagy pathways are divided into receptor-mediated mitophagy and ubiquitin-mediated mitophagy. During receptor-mediated mitophagy, under mitochondrial stress (i.e., hypoxia or depolarization), mitophagy receptors localize to the OMM. Both major mitophagy receptors, FUNDC1 and BNIP3L/NIX, facilitate phagophore formation. Ubiquitin-dependent mitophagy is PINK1/Parkin-dependent, and phosphorylation of both Parkin and ubiquitin is conducted by PINK1. Under Mt stress, PINK1 and Parkin decorate Mt with phosphor-ubiquitin chains. Mt covered in ubiquitin are recognized by multiple autophagy receptors that assemble the autophagosomal machinery for degradation of damaged Mt. LC3 is involved in both ubiquitin-dependent and receptor-mediated mitophagy.CC BY · PubMed Central
Figure 2 MSC/MSC-EV/Mt treatment of different injured organs induces Mt uptake by damaged cells and functional improvement of affected organs (Created with BioRender.com). Donation of healthy Mt by MSCs to injured donor cells of different organs corrects mitochondrial dysfunction of recipient cells (through MQC regulation) and activates metabolic and/or immunomodulatory pathways involved in restoration of tissue function. Oxidative stress is reduced, and Mϕ shifted to M2-like phenotype. On the other hand, Mt released from damaged or dying cells represent a key environmental factor that increases Mt drive, secretion of anti-inflammatory and pro-reparatory factors by MSCs. Legend: ↑ increase; ↓ decrease; gray arrows are pointing to the organs.
Figure 2 MSC/MSC-EV/Mt treatment of different injured organs induces Mt uptake by damaged cells and functional improvement of affected organs (Created with BioRender.com). Donation of healthy Mt by MSCs to injured donor cells of different organs corrects mitochondrial dysfunction of recipient cells (through MQC regulation) and activates metabolic and/or immunomodulatory pathways involved in restoration of tissue function. Oxidative stress is reduced, and Mϕ shifted to M2-like phenotype. On the other hand, Mt released from damaged or dying cells represent a key environmental factor that increases Mt drive, secretion of anti-inflammatory and pro-reparatory factors by MSCs. Legend: ↑ increase; ↓ decrease; gray arrows are pointing to the organs.CC BY · PubMed Central

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  1. Maumus, 2018, Mesenchymal Stem Cells and Regenerative Medicine: Future Perspectives in Osteoarthritis, Med. Sci., 34, 1092

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Metadata

Authors
Mukkala, A. N., Jerkic, M., Khan, Z., Szaszi, K., Kapus, A., & Rotstein, O.
Affiliations
  • St. Michael's Hospital (CA)
  • Unity Health Toronto, The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2023-10-31
Volume
24
Issue
21
Pages
15788
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms242115788
PMC
PMC10647450
OpenAlex
W4388048619
Cited by
45
References
233
Citations by year
2026: 10 · 2025: 19 · 2024: 16
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
Funders
  • Canadian Institutes of Health Research (CIHR) (#23766, PJT-180624, PJT-178152, AK2023)
  • Kidney Foundation of Canada (#23766, PJT-180624, PJT-178152, AK2023)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
mesenchymal stem cells, mitochondrial transfer, mitochondrial quality control, mitophagy, mitochondrial biogenesis, mitochondrial fission and fusion, PGC-1α, Parkin, mitofusins, Drp1, tunneling nanotubes, extracellular vesicles, organ damage, inflammation resolution, immunomodulation
MeSH terms
Humans, Inflammation, Mitochondria, Cell Membrane Structures, Nanotubes, Mesenchymal Stem Cells

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