Mitochondrial dysfunction and reactive oxygen species (ROS) play critical roles in disease processes from ischemic AKI, to immune response and inflammation, diabetes, obesity, metabolic syndrome, aging, neurodegenerative and cardiovascular diseases. Therefore, elucidating mechanisms of mitochondrial dysfunction is key to understanding the pathophysiology of many disease processes. Using the ischemia/reperfusion (I/R) kidney injury model to characterize mitochondrial pathways for kidney protection, we identified stanniocalcin-1 (STC1) as a potential therapeutic target. STC1 is a mitochondrial intracrine molecule (defined as an extracellular signaling molecule that enters cells, translocates to mitochondria and alters their function). STC1 activates AMPK, which in turn upregulates uncoupling proteins (UCPs) and SIRT3, promoting mitochondrial anti-oxidant defenses. Transgenic overexpression of STC1 confers resistance to IR kidney injury. The mechanism whereby intracrines such as STC1 are translocated to mitochondria is unknown. We have identified the multi-ligand receptor megalin as a trafficking vehicle for STC1 from the cell surface to mitochondria via the retrograde early endosome-to-Golgi. Megalin KO in cultured cells decreases the expression of SIRT3, diminishes mitochondrial respiration and glycolysis, and increases susceptibility to ischemic kidney injury. This proposal will examine the hypotheses that: megalin is critical for mitochondrial biology; KO of megalin aggravates ischemic kidney injury; and mitochondrial targeting of STC1 is required for STC1-mediated cytoprotection.
Aim 1 A will determine the phenotype of ischemia/reperfusion kidney injury in mice with doxycycline-inducible and tubular epithelium-specific knockout of megalin.
Aim 1 B will characterize the mitochondrial phenotype in cultured proximal tubule cells with megalin KO, at baseline and following hypoxia/reoxygenation.
Aim 2 A will determine whether mitochondrial targeting of STC1 is required for STC1-mediated cytoprotection in vitro.
Aim 2 B will determine whether mitochondrial targeting of STC1 is required for STC1-mediated cytoprotection in vivo. Our proposed studies will elucidate the role of megalin and STC1 in mitochondrial function and may offer fundamental insights into the pathogenesis of diseases where mitochondrial dysfunction is critical.

Public Health Relevance

Mitochondrial dysfunction and reactive oxygen species play important roles in many disease processes from acute kidney injury, to inflammation, diabetes, obesity, aging, neurodegenerative and cardiovascular diseases. The naturally occurring anti-oxidant protein stanniocalcin-1 protects the kidneys from ischemic damage. It is carried to the mitochondria by megalin, and the current proposal will examine mitochondrial targeting of stanniocalcin-1 by megalin and its impact on kidney protection.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX002006-05A2
Application #
9663407
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2014-04-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Michael E Debakey VA Medical Center
Department
Type
DUNS #
078446044
City
Houston
State
TX
Country
United States
Zip Code
77030
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