De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans

Deuse, T.; Hu, Xiaomeng; Agbor‐Enoh, Sean; Koch, Martina; Spitzer, Matthew H.; Gravina, Alessia; Alawi, Malik; Marishta, A.; Peters, Bjoern; Koşaloğlu‐Yalçın, Zeynep; Yang, Yanqin; Rajalingam, Raja; Wang, Dong; Nashan, Bjoern; Kiefmann, Rainer; Reichenspurner, Hermann; Valantine, Hannah A.; Weissman, Irving L.; Schrepfer, Sonja

doi:10.1038/s41587-019-0227-7

Cited by 88 publications

(72 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, neuromelanin-triggered NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signalling ( Wilms et al , 2003 ) and autophagy-mediated NLRP3 inflammasome activation ( Zhong et al , 2018 ) are established molecular mechanisms in Parkinson’s disease. Moreover, mtDNA variants were recently described to act as immunogenic neoepitopes ( Deuse et al , 2019 ). Thus, somatic mtDNA mutations, which have been previously documented in idiopathic Parkinson’s disease ( Bender et al , 2006 ), might constitute an additional parameter modulating cGAS-STING signalling and, in turn, IL6 levels.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Borsche

König

Delcambre

et al. 2020

Brain

135

102

View full text Add to dashboard Cite

There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Borsche

König

Delcambre

et al. 2020

Brain

135

102

View full text Add to dashboard Cite

show abstract

“…The genomic instability could also contribute to the immunogenicity of iPSC-derived autologous cells (Robertson et al, 2007;Zhao et al, 2011;de Almeida et al, 2014;Zhao et al, 2015;Todorova et al, 2016). Recent studies also demonstrate that mitochondrial DNA mutations in iPSCs contribute to the immunogenecity of iPSCs (Deuse et al, 2019). These safety concerns must be addressed before the clinical development of iPSC-based human cell therapy.…”

Section: Roles Of P53 In Induced Pluripotencymentioning

confidence: 99%

Functions of p53 in pluripotent stem cells

et al. 2019

Protein Cell

View full text Add to dashboard Cite

Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

show abstract

“…mtDNA SNVs identified by high-throughput sequencing were validated by two other platforms -digital droplet PCR and targeted sequencing (25). Approximately one-year post-transplantation, we collected recipient peripheral blood mononuclear cells (PBMCs) and used Elispot to determine allo-specific immune responses triggered by donor-derived peptides.…”

Section: Methodsmentioning

confidence: 99%

“…One-year post-transplantation, we collected whole blood and isolated PBMCs. We used Elispot to assay for interferon gamma (IFNγ) release as described elsewhere by Deuse and colleagues (25). The number of IFNγ-spots were compared for donor-derived and recipient-derived mt peptides.…”

Section: Methodsmentioning

confidence: 99%

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

Marishta

Yang

et al. 2020

Preprint

Self Cite

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

De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans

Cited by 88 publications

References 34 publications

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Functions of p53 in pluripotent stem cells

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

Contact Info

Product

Resources

About