*Purpose: Prolonged ischemia reperfusion injury (IRI) during organ transplantation activates innate immunity and potentiates adaptive immunity, leading to worse transplant outcomes. The mitochondria are particularly susceptible to ischemia. Among mitochondrial molecules with protective effects upon ischemia, the PPARγ coactivator-1α (PGC1α) has emerged as a major regulator of the mitochondrial biogenesis and metabolism. Whether PGC1α is protective in prolonged ischemia upon transplantation is unknown. To explore the role of PGC1α in the allograft, we used PGC1α-deficient animals as donors in a fully MHC mismatched cardiac transplant model.

*Methods: Pgc1α^+/+ or Pgc1α^−/− B6 hearts were harvested and transplanted into BALB/c recipients after immersion in HTK solution for 6h at 4ºC. On day 2 post-transplant, mice received a single dose of CTLA4Ig. On day 21 post-transplant, we isolated graft infiltrating cells and analyzed them by flow cytometry. Also, we compared metabolite profiles between Pgc1α^−/− and Pgc1α^+/+ heart allografts to identify PGC1α-controlled pathways.

*Results: Following prolonged ischemia, Pgc1α^−/− hearts had an accelerated rejection when compared to Pgc1α^+/+ controls (MST=70 vs >120 days, respectively, p=0.017). There was an increase in the percentage and numbers of both IFN-γ⁺-CD4⁺ (p<0.05) and -CD8⁺ T cells (p<0.01) in Pgc1α^−/− hearts compared to controls. In addition, Pgc1α^−/− hearts showed a higher infiltration of Ly6C^hi macrophages (p<0.05), indicating an enhancement of both innate and adaptive immunity in the absence of PGC1α in the allograft. Following prolonged ischemia, we found six differentially abundant metabolites. Among those, carnitine reduction in Pgc1α^–/– grafts supported mitochondrial involvement. PGC1α-deficient allografts showed elevated levels of glucuronic acid, aminoadipic acid and malonate with potential links to immune activation. Also, at baseline, Pgc1α^−/− hearts had more kynurenine and less niacinamide, aligned with the data from the Pgc1α^−/− kidney, which showed more inflammation upon ischemic injury.

*Conclusions: In summary, our data suggest that PGC1α induction has a protective role in cardiac transplantation following ischemia by decreasing innate and adaptive immunity, identifying a potential novel target for future therapies.

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