Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease that is associated with high mortality and affects both the general population and veterans. A key pathological feature of ischemic AKI is necrotic and apoptotic cell death in renal tubules. The long- term goal of Dr. Dong is to delineate the mechanism of tubular cell death in kidneys and discover new, effective strategies for the prevention and treatment of AKI. During the last grant period, Dr. Dong and colleagues revealed a striking morphological change of mitochondria during apoptosis, called mitochondrial fragmentation. Inhibition of mitochondrial fragmentation prevented apoptosis in renal tubules and ameliorated AKI, supporting a critical pathogenic role. Mechanistically, mitochondrial fragmentation requires the cleavage of both mitochondrial inner and outer membranes. Cleavage of the outer membrane involves the activation of Drp-1 and inactivation of Mitofusins; however, very little is known about cleavage of the inner membrane. Dr. Dong and colleagues have now demonstrated a role of Bax-interacting factor-1 (Bif-1) in mitochondrial fragmentation. Moreover, they have discovered the novel interaction of Bif-1 with prohibitin 2 (PHB2), a protein that may regulate mitochondrial inner membrane by sequestering OMA1 to prevent the proteolysis of OPA1, an inner membrane fusion protein. Based on these observations, they hypothesize that: During cellular stress, Bif-1 translocates to mitochondria and interacts with PHB2, resulting in the disruption of the prohibitin ring complex to release OMA1. OMA1 then has the access to OPA1 for proteolytic cleavage and inactivation, leading to the inhibition of inner membrane fusion to contribute to mitochondrial fragmentation. To test this hypothesis, they will: 1) determine the role of Bif-1 in prohibitin ring complex disruption, OPA1 proteolysis, mitochondrial damage and apoptosis during ischemic AKI; 2) elucidate the molecular interaction between Bif-1 and PHB2, and determine its role in mitochondrial regulation; 3) determine the role of OMA1 in OPA1 proteolysis, mitochondrial fragmentation and tubular cell apoptosis. This application will delineate the molecular mechanism of inner membrane cleavage in mitochondrial fragmentation and apoptosis. It may also lead to the development of novel therapeutic strategies for ischemic AKI and related diseases.
A broad range of clinical conditions including dehydration, hypotension, septic shock, trauma and operative arterial clamping leads to the reduction of blood flow to the kidneys, resulting in ischemic acute kidney injury (AKI) or renal failure. In the United States, over 200,000 cases of AKI are diagnosed each year with a direct medical expense in billions of dollars. Aging population, mirrored by veterans, is highly susceptible to AKI. Each year, more than 10,000 veterans develop AKI. AKI is also a common complication among military casualties in battle-fields and training camps. Particularly, ischemic AKI is associated with high mortality, over 50%. This application aims at the identification of the key molecular factors that mediate ischemic AKI. While being mechanistic, the research may lead to novel strategies for the prevention and treatment of this devastating disease, contributing significantly to the improvement of veterans' health.
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