# Megalin, mitochondrial intracrine signaling and the kidney

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2021 · —

## Abstract

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
1A will determine the phenotype of ischemia/reperfusion kidney injury in mice with doxycycline-inducible and
tubular epithelium-specific knockout of megalin. Aim 1B will characterize the mitochondrial phenotype in cultured
proximal tubule cells with megalin KO, at baseline and following hypoxia/reoxygenation. Aim 2A will determine
whether mitochondrial targeting of STC1 is required for STC1-mediated cytoprotection in vitro. Aim 2B 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.

## Key facts

- **NIH application ID:** 10085185
- **Project number:** 5I01BX002006-07
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** DAVID SHEIKH-HAMAD
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085185

## Citation

> US National Institutes of Health, RePORTER application 10085185, Megalin, mitochondrial intracrine signaling and the kidney (5I01BX002006-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085185. Licensed CC0.

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