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The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations. Mitochondrial DNA mutations in iPSCs can render them immunogenic.

Tissues derive ATP from two pathways—glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism 1 . In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras -mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect 2 , 3 ), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue’s major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP. As solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

Abstract 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 allo−specific 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. Competing Interest Statement The authors have declared no competing interest.