# Mechanism of ER Protein Misfolding-Induced Mitochondrial Dysfunction

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $614,427

## Abstract

PROJECT SUMMARY
The prevalence of non-alcoholic fatty liver disease (NAFLD) is almost 30% in the western world and is
expected to rise in the next decade. NAFLD is characterized by protein misfolding in the endoplasmic
reticulum (ER) activating the unfolded protein response (UPR). Prolonged ER stress conditions further lead
to oxidative stress, protein aggregation, organelle damage, cellular bioenergetic collapse, and eventually
cell death. Recent studies indicate that protein misfolding in the ER contributes to hepatocyte failure
associated with NAFLD, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC).
Through detailed characterization of hepatocyte function, our preliminary results lead us to propose that ER
protein misfolding causes mitochondrial dysfunction that leads to further protein misfolding culminating in
hepatocyte failure. Although previous studies demonstrated that protein misfolding in the ER of hepatocytes
is associated with metabolic syndrome and NAFLD, there has never been a careful characterization of how
ER protein misfolding causes catastrophic cellular events leading to oxidative damage, fibrosis and cell
death. We have shown that misfolding of coagulation factor VIII (FVIII) in the ER disrupts complex 1 of the
electron transport chain. Amazingly, we demonstrated that treatment with a mitochondrial-targeted
antioxidant corrects he defective mitochondrial function and also improves FVIII folding in the ER in cell
culture. This unprecedented finding indicates an unappreciated association between ER protein misfolding
and defective mitochondrial bioenergetics. In the proposed studies, we will use two separate models to
induce ER stress in vivo in hepatocytes; (i) excess nutrition of a high fructose diet, or (ii) expression of FVIII
to elucidate how ER protein misfolding disrupts mitochondrial bioenergetics and dynamics. Presently,
ongoing clinical studies are using viral delivery of FVIII to hepatocytes in hemophilia A patients.
Furthermore, we will apply non-biased technologies of metabolomics and RNA-Seq using novel genetic
murine models to elucidate how protein misfolding causes Ca2+ leak from the ER and entry into the
mitochondrial matrix to disrupt mitochondrial bioenergetics and/or dynamics. Evidence supports that ER
protein misfolding and defective mitochondrial function exist in all degenerative diseases. In addition,
extensive findings demonstrate that protein misfolding in the ER is associated with liver failure in a number
of common acute conditions including viral infection, ethanol toxicity, acetaminophen toxicity and ischemia
reperfusion injury. Our fundamental novel exploration into unchartered territory will undoubtedly generate
new hypotheses concerning the impact of ER protein misfolding on the mitochondrial electron transport
chain. The studies will provide fundamental mechanistic insight into how ER and mitochondrial functions are
reciprocally regulated and lead to novel therapies for N...

## Key facts

- **NIH application ID:** 9994742
- **Project number:** 5R01DK113171-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** RANDAL J. KAUFMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $614,427
- **Award type:** 5
- **Project period:** 2017-09-18 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994742

## Citation

> US National Institutes of Health, RePORTER application 9994742, Mechanism of ER Protein Misfolding-Induced Mitochondrial Dysfunction (5R01DK113171-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9994742. Licensed CC0.

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