Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction

Pollara, Justin; Edwards, R. Whitney; Lin, Li-Wen; Bendersky, Victoria A.; Brennan, Todd V.

doi:10.1172/jci.insight.121622

Cited by 75 publications

(60 citation statements)

References 62 publications

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“…Emerging evidence suggests that during necrotic cell injury, mitochondrial damage-associated molecular patterns (DAMPS), also called alarmins, are released (Collins, Hajizadeh, Holme, Jonsson, & Tarkowski, 2004;Pollara et al, 2018 ;Zhang et al, 2010). Some DAMPS share highly conserved DNA motifs with bacterial pathogen-associated molecular patterns, which are present on pathogenic bacteria and some viruses (Pollara et al, 2018;Zhang et al, 2010). Both bind and activate PRRs such as Toll-like receptors and trigger an innate immune response (Zhang et al, 2010).…”

Section: Mitochondrial Dnamentioning

confidence: 99%

“…• DAMPS; activate PRR and trigger innate immune response (Collins et al, 2004;Pollara et al, 2018;Zhang et al, 2010) Gal epitope • Complement activation • Hyper acute rejection • Allergic reaction; anaphylactic shock (Commins et al, 2009;Kollmann et al, 2017;Lexer et al, 1986) MHC…”

Section: Specific Elementsmentioning

confidence: 99%

“…For those who do receive an organ transplant, the lifelong commitment to immunosuppressants may result in a significant burden on their quality of life. In addition, some organ transplants have a failure rate of 25–40% after 5 years (Pollara, Edwards, Lin, Bendersky, & Brennan, ). Hence, there is an urgent need for new strategies to overcome the shortage of organs available for transplantation as well as to improve the outcome and the quality of life of these patients.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Limitations of recellularized biological scaffolds for human transplantation

Bilodeau

Goltsis

Rogers

et al. 2020

J Tissue Eng Regen Med

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A shortage of donor organs for transplantation and the dependence of the recipients on immunosuppressive therapy have motivated researchers to consider alternative regenerative approaches. The answer may reside in acellular scaffolds generated from cadaveric human and animal tissues. Acellular scaffolds are expected to preserve the architectural and mechanical properties of the original organ, permitting cell attachment, growth, and differentiation. Although theoretically, the use of acellular scaffolds for transplantation should pose no threat to the recipient's immune system, experimental data have revealed significant immune responses to allogeneic and xenogeneic transplanted scaffolds. Herein, we review the various factors of the scaffold that could trigger an inflammatory and/or immune response, thereby compromising its use for human transplant therapy. In addition, we provide an overview of the major cell types that have been considered for recellularization of the scaffold and their potential contribution to triggering an immune response.

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Section: Mitochondrial Dnamentioning

confidence: 99%

Section: Specific Elementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Limitations of recellularized biological scaffolds for human transplantation

Bilodeau

Goltsis

Rogers

et al. 2020

J Tissue Eng Regen Med

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“…Pollara et al recently demonstrated that mtDNA levels in the donor circulation are associated with early allograft dysfunction in liver recipients, suggesting the inflammatory potential of donor-derived DAMPs 40. Pollara et al recently demonstrated that mtDNA levels in the donor circulation are associated with early allograft dysfunction in liver recipients, suggesting the inflammatory potential of donor-derived DAMPs 40.…”

mentioning

confidence: 99%

“…Second, we did not have access to donor-derived tissues for most of our transplants, and therefore it was not possible to differentiate donor and recipient mtDNA. Pollara et al recently demonstrated that mtDNA levels in the donor circulation are associated with early allograft dysfunction in liver recipients, suggesting the inflammatory potential of donor-derived DAMPs 40. Although in our mouse PGD model we demonstrated that most damaged mitochondria release was of donor origin, the degree to which donor-derived mtDAMPs Finally, it may be possible that blood transfusions, commonly used in the lung transplant procedure, may alter mtDNA measurements, as recent work has shown they can accumulate in stored blood products 41.…”

mentioning

confidence: 99%

Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction

Scozzi

Ibrahim

Liao

et al. 2019

American Journal of Transplantation

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Primary graft dysfunction (PGD) is a major limitation in short-and long-term lung transplant survival. Recent work has shown that mitochondrial damage-associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)-induced pulmonary edema. Therefore, our data demonstrate an association between mt-DAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage. K E Y W O R D Sanimal models, basic (laboratory) research/science, cellular biology, clinical research/practice, immunobiology, innate immunity, ischemia-reperfusion injury (IRI), lung (allograft) function/ dysfunction, lung transplantation/pulmonology, mouse | 1465 SCOZZI et al.

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Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis

Cai

Zhang

et al. 2022

Advanced Science

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Mitochondria are the powerhouse of eukaryotic cells, which regulate cell metabolism and differentiation. Recently, mitochondrial transfer between cells has been shown to direct recipient cell fate. However, it is unclear whether mitochondria can translocate to stem cells and whether this transfer alters stem cell fate. Here, mesenchymal stem cell (MSC) regulation is examined by macrophages in the bone marrow environment. It is found that macrophages promote osteogenic differentiation of MSCs by delivering mitochondria to MSCs. However, under osteoporotic conditions, macrophages with altered phenotypes, and metabolic statuses release oxidatively damaged mitochondria. Increased mitochondrial transfer of M1-like macrophages to MSCs triggers a reactive oxygen species burst, which leads to metabolic remodeling. It is showed that abnormal metabolism in MSCs is caused by the abnormal succinate accumulation, which is a key factor in abnormal osteogenic differentiation. These results reveal that mitochondrial transfer from macrophages to MSCs allows metabolic crosstalk to regulate bone homeostasis. This mechanism identifies a potential target for the treatment of osteoporosis.

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Circulating mitochondria in deceased organ donors are associated with immune activation and early allograft dysfunction

Cited by 75 publications

References 62 publications

Limitations of recellularized biological scaffolds for human transplantation

Limitations of recellularized biological scaffolds for human transplantation

Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction

Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis

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