# Dissecting the Molecular Mechanisms of Selective Autophagy

> **NIH NIH R35** · DARTMOUTH COLLEGE · 2024 · $442,800

## Abstract

Autophagy is a cellular process in which cytosolic material is captured in double-membrane
vesicles, termed autophagosomes. Subsequently, autophagosomes fuse with the vacuole, in
yeast, or lysosomes, in mammalian cells, leading to the degradation of the captured contents.
Autophagy can capture a diversity of cytosolic cargos, including organelles, large protein
aggregates and intracellular pathogens. As such, autophagy plays critical roles in maintaining
organelle quality, preventing the accumulation of protein aggregates and clearing intracellular
pathogens. Therefore, defects in autophagy have been associated with various human diseases,
including cancer, neurodegenerative disease and inflammatory disease. During autophagy, cargo
can be captured via a non-selective or selective mechanism. In selective autophagy, cargos are
identified by selective autophagy receptors (SARs). SARs are either soluble cytosolic proteins
recruited to the cargo upon autophagy initiation or integral membrane proteins embedded in the
organelle membrane that will become a cargo for selective autophagy. While the mechanisms by
which cytosolic SARs initiate selective autophagy have become increasingly clear, the
mechanisms by which integral membrane SARs coordinate with the autophagy machinery to
initiate selective autophagy are still not well understood.
The proposed work will use mitochondrial autophagy (mitophagy) in yeast as a model system to
investigate the mechanisms by which integral membrane SARs coordinate with the autophagy
machinery to initiate selective autophagy. Mitophagy in yeast is an ideal system to study selective
autophagy initiation as yeast have only a single SAR for mitochondria, termed Atg32. In contrast,
mammalian cells have five integral membrane SARs for mitochondria making it more challenging
to interpret knockdown or mutagenesis studies of any individual SARs as other related SARs may
compensate. This proposal will utilize a cross-disciplinary approach combining cell biology, lipid
biochemistry, biochemical reconstitution and structural biology to study mitophagy initiation. The
proposed work will help develop a molecular understanding of the mechanisms of selective
autophagy initiation by integral membrane SARs, provide a starting point for studying other
integral membrane SARs using biochemical approaches and provide novel methods for studying
these systems.

## Key facts

- **NIH application ID:** 10765072
- **Project number:** 2R35GM128663-06
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Michael Joseph Ragusa
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,800
- **Award type:** 2
- **Project period:** 2018-09-14 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765072

## Citation

> US National Institutes of Health, RePORTER application 10765072, Dissecting the Molecular Mechanisms of Selective Autophagy (2R35GM128663-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10765072. Licensed CC0.

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