# Regulation of mitochondrial dynamics by ERAD

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $390,000

## Abstract

Regulation of Mitochondrial Dynamics by ERAD
ABSTRACT
Cells face a complex challenge of balancing protein folding and degradation in the endoplasmic reticulum (ER),
a multifunctional organelle that is central to human health. Further, dysregulation of this balance accounts for
the pathogenesis of many human diseases. ER-associated degradation (ERAD) is a principal quality-control
mechanism used by the cells to target misfolded proteins in the ER for proteasomal degradation in the cytosol.
However, the physiological function of distinct mammalian ERAD components remain largely unclear. In the
last several years, we have explored the physiological importance of cell type-specific ERAD in normal
physiology and disease, and have identified molecular substrates and pathways underpinning ERAD-
associated pathophysiology. While ERAD expression is known to be controlled by IRE1a signaling of the UPR,
we recently discovered a negative feedback loop in which the Sel1L-Hrd1 protein complex of mammalian
ERAD restrains IRE1a signaling and activation under the steady state by targeting IRE1a for proteasomal
degradation. This study demonstrates an intimate crosstalk between the two most conserved ER quality-
control systems. Surprisingly, our recent data in brown adipocytes reveals that Sel1L-Hrd1 ERAD may regulate
mitochondrial dynamics, in part via IRE1a. Sel1L-deficient brown adipocytes exhibit a profound morphological
alteration of mitochondria in response to cold exposure, which can be partially rescued upon the deletion of
IRE1a. One of the major goals for the next five years is to delineate the molecular mechanism underlying the
regulation of mitochondrial dynamics by ERAD by testing the overarching hypothesis that Sel1L-Hrd1 ERAD
regulates mitochondrial dynamics and function via IRE1a. We will explore whether and how the “Sel1L-
Hrd1 ERAD-IRE1a” axis of ER quality control machineries exerts control over mitochondrial fission-fusion
balance. This study may not only reveal the significance of an “ERAD-UPR” crosstalk at the core of normal
cellular function and physiology, but may also provide exciting insights into the organelle crosstalk, a largely
mysterious process.
With funding support from NIGMS, we have made great progress towards the understanding of the ERAD-
UPR biology in mammals in the past several years. Hence, we are uniquely positioned to lead this project with
innovation, passion and dedication to scientific discovery. The R35 grant mechanism will give us the
intellectual freedom, time and resources to direct our energy for exploration into discovery and will open up
new directions to provide unprecedented insights into the role of ER quality-control machineries in
mitochondrial biology.

## Key facts

- **NIH application ID:** 9899265
- **Project number:** 5R35GM130292-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ling Qi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899265

## Citation

> US National Institutes of Health, RePORTER application 9899265, Regulation of mitochondrial dynamics by ERAD (5R35GM130292-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899265. Licensed CC0.

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