# Removal of damaged mitochondria by alternative autophagy

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $600,995

## Abstract

Autophagy is a major mechanism of degradation of damaged mitochondria. Without elimination of damaged
mitochondria, depolarized mitochondria and reactive oxygen species (ROS) rapidly affect healthy
mitochondria, leading to wide-spread mitochondrial dysfunction and cell death. Understanding how damaged
mitochondria are removed will provide a key to achieving healthier mitochondria in cardiomyocytes (CMs) and
developing novel treatments for heart failure. Although it is believed that damaged mitochondria are degraded
primarily by Pink1-Parkin-mediated mitophagy, we have discovered that CMs degrade mitochondria through an
Atg7-independent and Ulk1-dependent form of autophagy that is homologous to the “alternative” autophagy
previously reported by Nishida, and that this form of autophagy plays a significant role in the elimination of
damaged mitochondria in response to starvation. However, neither the molecular mechanism nor the functional
significance of mitophagy mediated through alternative autophagy has been clearly established in CMs yet.
Thus, the goal of this project is to demonstrate the functional significance of alternative autophagy in
eliminating damaged mitochondria in the heart in response to relevant stresses and to elucidate the underlying
molecular mechanisms. Hypothesis 1: In response to myocardial ischemia, the heart activates Atg7-
independent/Ulk1-dependent alternative autophagy, which plays an essential role in mediating the clearance of
damaged mitochondria and protects the heart from myocardial ischemia. Hypothesis 2: Ulk1 phosphorylated
at Ser555 acts as a scaffold to induce Rab9 interaction for autophagosome formation and phosphorylation of
Drp1 at Ser616 for mitochondrial fission, both of which are important in mediating mitochondrial autophagy in
response to myocardial ischemia. We will: Aim 1: Demonstrate that the atg7-independent and ulk1-dependent
alternative autophagy is activated by myocardial ischemia. Evaluate whether alternative autophagy protects
the heart during myocardial ischemia. To this end, we will use cardiac-specific atg7- and ulk1-knockout mice,
electron microscopy, specific reporters of alternative autophagy and mitochondrial autophagy, and functional
analyses of mitochondria. We will show that damaged mitochondria are degraded primarily through alternative
autophagy during myocardial ischemia. Aim 2: Evaluate whether phosphorylation of Ulk1 at Ser555 plays an
essential role in mediating alternative autophagy and cardioprotection during myocardial ischemia by
stimulating interaction with Rab9 and Ser616-phosphorylated Drp1. To this end, we will use loss-of-function
and knock-in mouse models and unique and reliable reporters for alternative autophagy and lysosomal
degradation of mitochondria. The knowledge obtained from this aim should lead to development of specific
interventions to modulate mitophagy during myocardial ischemia. In summary, our study will demonstrate that
alternative autophagy is a novel...

## Key facts

- **NIH application ID:** 9978602
- **Project number:** 5R01HL138720-04
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Junichi Sadoshima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $600,995
- **Award type:** 5
- **Project period:** 2017-08-15 → 2021-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978602

## Citation

> US National Institutes of Health, RePORTER application 9978602, Removal of damaged mitochondria by alternative autophagy (5R01HL138720-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9978602. Licensed CC0.

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