BACKGROUND
1. The critical link between hyperoxia, ALI, and mitochondrial dysfunction
Recent reports identify that annually, 58 to 78 cases of ALI or acute respiratory distress syndrome (ARDS) occur per 100,000 population globally, with approximately 200,000 adult cases occurring in the U.S. alone (23). Current scientific evidence pinpoints reactive oxygen species (ROS) as the key pathological event (9, 10, 24-26). Hyperoxia is a commonly used treatment for patients experiencing acute and chronic cardiovascular and pulmonary diseases (1-3). Unfortunately, prolonged use of the treatment has been shown to result in accumulation of ROS and therefore trigger acute lung injury (ALI). Among the most critical events in the pathology of hyperoxic …show more content…
It is known that depletion of mitochondrial AKAP121 is sufficient to cause mitochondrial fragmentation and cell death (46). Previously, we identified that there is an association between mitochondrial fragmentation and HALI, but the mechanism remains unclear. Now, our preliminary data show that isolated type II AECs from SOCS-1 deficient mice display a reduction of AKAP121 levels, when compared to WT AECs under normoxia. Further investigation revealed that hyperoxic depletion of AKAP121 can be counteracted by introduction of SOCS-1. In this proposal, we hypothesize that Siah2 is the self-regulating molecule responsible for the depletion of AKAP121 under hyperoxic conditions, and that Siah2 may be eliminated by SOCS-1. The overarching goal of this study is to clarify the mechanism affecting AKAP121 protein levels in hyperoxic conditions, and investigate whether regulation of SOCS-1 can restore AKAP121 levels and therefore prevent mitochondrial …show more content…
Evidence shows that Siah2 is upregulated in both hypoxia and hyperoxia, therefore leading to degradation of AKAP121. It is also known that Siah2 is capable of disrupting mitochondrial membrane potential and stability by degrading AKAP121. Our preliminary data reveals that loss of Siah2 activity is sufficient to prevent degradation of AKAP121. However, it is not known if SOCS-1 is involved in the control of Siah2 expression. Previously we identified that SOCS-1 is capable of triggering ubiquitination of target proteins. Our preliminary data demonstrates a decrease in Siah2 levels in the presence of SOCS-1. Based on this we hypothesize that SOCS-1 wields the ability to impede the ubiquitin activity of Siah2 and thereby avert the depletion of AKAP121. Determining whether Siah2 is the intermediate molecule responsible for the interaction between AKAP121 and SOCS-1 will allow for elucidation of the mechanism of AKAP121-mediated protection against
1. The critical link between hyperoxia, ALI, and mitochondrial dysfunction
Recent reports identify that annually, 58 to 78 cases of ALI or acute respiratory distress syndrome (ARDS) occur per 100,000 population globally, with approximately 200,000 adult cases occurring in the U.S. alone (23). Current scientific evidence pinpoints reactive oxygen species (ROS) as the key pathological event (9, 10, 24-26). Hyperoxia is a commonly used treatment for patients experiencing acute and chronic cardiovascular and pulmonary diseases (1-3). Unfortunately, prolonged use of the treatment has been shown to result in accumulation of ROS and therefore trigger acute lung injury (ALI). Among the most critical events in the pathology of hyperoxic …show more content…
It is known that depletion of mitochondrial AKAP121 is sufficient to cause mitochondrial fragmentation and cell death (46). Previously, we identified that there is an association between mitochondrial fragmentation and HALI, but the mechanism remains unclear. Now, our preliminary data show that isolated type II AECs from SOCS-1 deficient mice display a reduction of AKAP121 levels, when compared to WT AECs under normoxia. Further investigation revealed that hyperoxic depletion of AKAP121 can be counteracted by introduction of SOCS-1. In this proposal, we hypothesize that Siah2 is the self-regulating molecule responsible for the depletion of AKAP121 under hyperoxic conditions, and that Siah2 may be eliminated by SOCS-1. The overarching goal of this study is to clarify the mechanism affecting AKAP121 protein levels in hyperoxic conditions, and investigate whether regulation of SOCS-1 can restore AKAP121 levels and therefore prevent mitochondrial …show more content…
Evidence shows that Siah2 is upregulated in both hypoxia and hyperoxia, therefore leading to degradation of AKAP121. It is also known that Siah2 is capable of disrupting mitochondrial membrane potential and stability by degrading AKAP121. Our preliminary data reveals that loss of Siah2 activity is sufficient to prevent degradation of AKAP121. However, it is not known if SOCS-1 is involved in the control of Siah2 expression. Previously we identified that SOCS-1 is capable of triggering ubiquitination of target proteins. Our preliminary data demonstrates a decrease in Siah2 levels in the presence of SOCS-1. Based on this we hypothesize that SOCS-1 wields the ability to impede the ubiquitin activity of Siah2 and thereby avert the depletion of AKAP121. Determining whether Siah2 is the intermediate molecule responsible for the interaction between AKAP121 and SOCS-1 will allow for elucidation of the mechanism of AKAP121-mediated protection against