# Role of the Endosomal-Lysosomal Pathway in Mitochondrial Quality Control

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $387,500

## Abstract

Project Summary
Mitochondrial dysfunction in cardiac myocytes occurs early in the pathogenesis of heart failure. In the heart,
the primary function of mitochondria is to meet the high energy demand of the beating myocytes by providing
ATP through oxidative phosphorylation. However, mitochondria can quickly change into death–promoting
organelles. In response to changes in the intracellular environment, they can become excessive producers of
reactive oxygen species and release pro-death proteins. Not surprisingly, cells have developed defense
mechanisms against aberrant mitochondria that can cause harm to it. The ability of a cell to repair itself and
prevent unnecessary death is particularly important in a post-mitotic cell such as a myocyte that cannot be
easily replaced. Studies have found that dysfunctional mitochondria can be sequestered by autophagosomes
and subsequently delivered to lysosomes for degradation. However, the mechanism and regulation of
mitochondrial removal are not well characterized and whether additional mechanisms of mitochondrial
clearance exist is currently unclear. We have previously found that the E3 ubiquitin ligase Parkin plays an
important role in clearing dysfunctional mitochondria in the heart in response to stress and lack of Parkin leads
to accumulation of dysfunctional mitochondria after a myocardial infarction. Parkin is known to induce
autophagy of mitochondria but our preliminary studies have uncovered evidence that Parkin can also promote
clearance of mitochondria via an autophagy-independent mechanism. In this proposal, we will explore the
hypothesis that the small GTPase Rab5 and the endosomal degradation pathway play an important role in
clearing dysfunctional mitochondria in myocytes. This hypotheses will be tested with two aims. Aim 1 will
define the functional importance of Rab5 and endosomal-mediated mitochondrial clearance in myocytes in
vitro and in vivo. We will also examine the relationships between the endosomal pathway and
traditional/alternative autophagy pathways in the heart. In Aim 2, we will delineate the role of Beclin1 in
initiating the endosomal pathway in response to mitochondrial damage. We will examine whether Beclin1
regulates activation of the endosomal degradation pathway in response to cellular stress by forming a specific
pro-endosomal complex with Rab5 and Vps34. Loss-of-function studies in vitro and in vivo using unique
cardiac specific inducible Beclin1 deficient mice will be utilized to confirm the functional importance of Beclin1
initiating formation of early endosomes in response to mitochondrial damage and stress. These studies will
provide important novel insight into how dysfunctional and potentially dangerous mitochondria are cleared in
the heart. These studies will also provide insights into new potential therapeutic targets in this pathway.

## Key facts

- **NIH application ID:** 9917812
- **Project number:** 5R01HL138560-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Asa B. Gustafsson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917812

## Citation

> US National Institutes of Health, RePORTER application 9917812, Role of the Endosomal-Lysosomal Pathway in Mitochondrial Quality Control (5R01HL138560-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9917812. Licensed CC0.

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