When it comes to heart transplantation, donation after brain death (DBD) has become the standard ofcare as this method is supported by many advantages, mainly due to the possibility to easily assessdonor heart function before retrieval and sensibly shorten the detrimental period of warm ischemia.Lately, however, the ever-increasing number of patients in waitlist for heart transplantation haspushed the interest of researchers to find new methods to increase the donor pool [1], including heartdonation after cardiocirculatory death (DCD). The latter, nonetheless, shows several disadvantagesincluding a longer period of warm ischemia, long-term outcomes uncertainty, and lack ofstandardized reliable biomarkers and physiological parameters predictive of function andtransplantability of DCD hearts [2]. One of the earliest cardiomyocytes degenerations starting aftercardiac death is borne by mitochondria that are involved in some distinct types of cell death.Therefore, studying such events may help better understanding the physiological processesunderlying DCD heart transplantability, eventually leading to definition of useful biomarkers. Toachieve this, the focus of this work was the F₁Fₒ-ATPase complex, considered as the leading candidateresponsible for the opening of a channel though the inner membrane called mitochondrialpermeability transition pore (mPTP) when the natural cofactor (Mg²+) is replaced with the physio-pathological cofactor (Ca²+) [3]. Specifically, trying to preserve mitochondrial bioener getics andintegrity, we assessed the efficacy of IO-SMPs (inside-out submitochondrial particles) obtained byswine hearts isolated by stepwise centrifugation from mitochondria [4], on an ex-vivo porcine modelof DCD heart (20 min of no touch after cardiac arrest followed by 2h of warm ischemia). Weevaluated the effect of IO-SMPs on Oxidative Phosphorylation and their influence on mitochondriacalcium retention capacity (CRC), an indirect index of mPTP opening, as already highlighted in otherstudies. Studies are currently ongoing, but the preliminary results show that IO-SMPs are capable ofdelaying the mPTP opening when swine heart mitochondria are exposed to Ca²+. Overall, this studyrepresents a first step towards an in-depth characterization of the physiological process activated bya prolonged warm ischemia within mitochondria, and investigates the potential beneficial effects ofIO-SMPs, that may be applicable to all DCD solid organs
EFFECTS OF INSIDE-OUT SUBMITOCHONDRIAL PARTICLES (IO-SMPS) ON MITOCHONDRIA ISOLATED FROM A PORCINE EX VIVO MODEL OF DONATION AFTER CARDIOCIRCULATORY DEATH (DCD) HEART
Cristina Algieri;
2023-01-01
Abstract
When it comes to heart transplantation, donation after brain death (DBD) has become the standard ofcare as this method is supported by many advantages, mainly due to the possibility to easily assessdonor heart function before retrieval and sensibly shorten the detrimental period of warm ischemia.Lately, however, the ever-increasing number of patients in waitlist for heart transplantation haspushed the interest of researchers to find new methods to increase the donor pool [1], including heartdonation after cardiocirculatory death (DCD). The latter, nonetheless, shows several disadvantagesincluding a longer period of warm ischemia, long-term outcomes uncertainty, and lack ofstandardized reliable biomarkers and physiological parameters predictive of function andtransplantability of DCD hearts [2]. One of the earliest cardiomyocytes degenerations starting aftercardiac death is borne by mitochondria that are involved in some distinct types of cell death.Therefore, studying such events may help better understanding the physiological processesunderlying DCD heart transplantability, eventually leading to definition of useful biomarkers. Toachieve this, the focus of this work was the F₁Fₒ-ATPase complex, considered as the leading candidateresponsible for the opening of a channel though the inner membrane called mitochondrialpermeability transition pore (mPTP) when the natural cofactor (Mg²+) is replaced with the physio-pathological cofactor (Ca²+) [3]. Specifically, trying to preserve mitochondrial bioener getics andintegrity, we assessed the efficacy of IO-SMPs (inside-out submitochondrial particles) obtained byswine hearts isolated by stepwise centrifugation from mitochondria [4], on an ex-vivo porcine modelof DCD heart (20 min of no touch after cardiac arrest followed by 2h of warm ischemia). Weevaluated the effect of IO-SMPs on Oxidative Phosphorylation and their influence on mitochondriacalcium retention capacity (CRC), an indirect index of mPTP opening, as already highlighted in otherstudies. Studies are currently ongoing, but the preliminary results show that IO-SMPs are capable ofdelaying the mPTP opening when swine heart mitochondria are exposed to Ca²+. Overall, this studyrepresents a first step towards an in-depth characterization of the physiological process activated bya prolonged warm ischemia within mitochondria, and investigates the potential beneficial effects ofIO-SMPs, that may be applicable to all DCD solid organsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
