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

Scozzi, Davide; Ibrahim, Mohsen; Liao, Fuyi; Lin, Xue; Hsiao, Hsi Min; Hachem, Ramsey R.; Tague, Laneshia K.; Rícci, Alberto; Kulkarni, Hrishikesh S.; Huang, Howard J.; Sugimoto, Seiichiro; Krupnick, Alexander S.; Kreisel, Daniel; Gelman, Andrew E.

doi:10.1111/ajt.15232

Cited by 49 publications

(38 citation statements)

References 53 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reasons for this incongruence are not clear. However, when compared to MT-CYTB, we generally detected lower copy numbers for MT-COX3, suggesting the possibility that this part of mitochondria genome is more intrinsically unstable when exposed to plasma (Scozzi et al, 2019).…”

Section: Discussionmentioning

confidence: 71%

“…Finally, MT DAMPs, unlike other inflammatory markers linked to poor outcomes of COVID-19 afflicted patients, have been reported to directly cause acute pulmonary dysfunction and tissue damage (Lee et al, 2017). Administration of MT DAMPs into the blood stream or pulmonary airways of rodents promotes acute lung injury mediated by neutrophil chemotaxis and reactive oxygen species generation to mitochondrial formylated peptides (Hauser et al, 2010;Scozzi et al, 2019). In these studies, the formylated peptide receptor-1 inhibitor cyclosporine H was shown to inhibit MT DAMP-mediated acute lung injury.…”

Section: Discussionmentioning

confidence: 99%

“…To assess MT-DNA levels in COVID-19 patients we utilized a previously established insitu quantitative PCR method (Scozzi et al, 2019) to measure the accumulation of fragments derived from the mitochondrial encoded gene cytochrome b (MT-CYTB) within cell-free circulating plasma. Plasma MT-CYTB levels were elevated in those subjects who died from n=25)] compared to those who survived [7.082 (6.650 -7.693), n=72, p=0.009, Figure 2A] and were associated with an increased risk for mortality on univariate logistic regression (OR 1.960, 95% CI 1.236 -3.28, p = 0.006).…”

Section: Covid-19 Patients With High Circulating Mt-dna Are At Highermentioning

confidence: 99%

“…Mitochondrial DNA (MT-DNA) is a member of a group of mitochondrial DAMPs (MT-DAMPs) released by injured or dying cells and is recognized by TLR9 due to encoded hypomethylated CpG motifs reminiscent of an ancestral bacterial origin (Zhang et al, 2010). MT-DNA levels have been previously shown to be elevated in the plasma of patients that develop ARDS and multi-organ dysfunction during sepsis, as well as during sterile injury including trauma, hemorrhagic shock and ischemiareperfusion (Faust et al, 2020;Hauser et al, 2010;Nakahira et al, 2013;Puskarich et al, 2012;Scozzi et al, 2019;Simmons et al, 2013). The release of MT-DNA is often accompanied by the release of other MT-DAMPs, such as N-formylated peptides, cytochrome c and cardiolipin, which collectively engage multiple TLRs and the Nformylated peptide receptor-1 that in turn not only induce inflammatory cytokine expression (Grazioli and Pugin, 2018;Wu et al, 2019;Zhang et al, 2014) but also the generation of reactive oxygen species and the facilitation of neutrophil trafficking and activation (Dorward et al, 2017;Nakayama and Otsu, 2018;Scozzi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

Scozzi

Cano

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

SUMMARYMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.

show abstract

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Covid-19 Patients With High Circulating Mt-dna Are At Highermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

Scozzi

Cano

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Release of mitochondrial content exposes transplant recipients to donor-derived proteins and mtDNA --a very potent DAMP (33,34). Scozzi and colleagues, as well as others (35), have described the association of circulating mtDNA with severe primary graft dysfunction after lung transplantation and proposed that the graft injury is coupled with neutrophil trafficking (36). We demonstrate that mtDNA peptide variants elicit allo-specific immune responses, which may potentially contribute to allograft rejection.…”

Section: Discussionmentioning

confidence: 56%

Donor-derived mitochondrial DNA variant peptides elicit allo-specific immune response in transplant patients

Marishta

Yang

et al. 2020

Preprint

View full text Add to dashboard Cite

BACKGROUND: Mitochondrial DNA (mtDNA) nonsynonymous single nucleotide variants (SNVs) between transplant donor stem cells and recipient trigger alloimmune responses and transplant rejection. Whether mt SNVs trigger alloimmune responses in solid-organ transplantation remains unknown, particularly in the background of immunodominant human leukocyte antigens mismatches. This study characterizes mtDNA SNVs and tests if donor-derived mitochondrial peptides trigger alloimmune responses in solid-organ transplantation. METHODS: To count and compare SNVs between donor and recipient (D-R) lung transplant pairs (n = 163), mtDNA was isolated from pre-transplant D-R blood and sequenced. The number of SNVs was compared for D-R demographic groups. We identified nonsynonymous SNVs, constructed 20mer peptides with donor-or recipient-derived amino acid sequences, and used ELISpot assay to test allospecific immune response by interferon gamma (IFNγ) release. To test if similar phenomena occur in other solid-organ transplants, we repeated the analyses in 19 heart transplant D-R pairs. RESULTS: We identified a median of 39 mtDNA SNVs (IQR= 32 -53) per D-R lung transplant pair, of which a median of 6 (IQR = 4 -9) SNVs were nonsynonymous. SNVs were predominantly located at MT-CYB, MT-ATP6, and MT-ND3 genes. The number of SNVs was higher in D-R race non-concordant pairs than in race-concordant pairs, p = 0.015. Donor-derived mt peptides triggered a 19.8-fold higher IFNγ release compared to recipient-derived peptide, p<0.001. Similar findings were observed in heart transplant patients. CONCLUSIONS: Donor-derived mitochondrial peptides trigger allo-specific immune responses after solid-organ transplantation.

show abstract

Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis

Cai

Zhang

et al. 2022

Advanced Science

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 49 publications

References 53 publications

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

Donor-derived mitochondrial DNA variant peptides elicit allo-specific immune response in transplant patients

Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis

Contact Info

Product

Resources

About