# Quality Control of Mitochondrial Nutrient Transporters

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

PROJECT SUMMARY/ABSTRACT
 Mitochondria are central to cellular metabolism. They produce energy through oxidative
phosphorylation, and participate in the metabolism of amino acids, heme, iron-sulfur clusters, lipids, and other
essential cellular metabolites. Alteration in mitochondria function is linked to many diseases, including cancer,
diabetes, and numerous neurodegenerative disorders. The majority of the biosynthetic reactions mitochondria
participate in occur within the matrix of the mitochondria, which is bounded by two membranes: a permeable
outer membrane, and an impermeable inner membrane. Cellular metabolites crucial for these reactions are
transported across the inner mitochondrial membrane through nutrient carriers, the largest class of which is the
mitochondrial carrier family. Despite their central importance in cellular metabolism, very little is understood
about how cells regulate the levels of mitochondrial metabolite transporters to control nutrient
compartmentalization. Using yeast as a model system, we recently found that mitochondrial function is
intimately linked to the cytoplasmic pool of amino acids. Amino acids are typically stored in the vacuole or
lysosome at high levels. However, disruption of efficient storage capability of this organelle leads to rapid
mitochondrial dysfunction, likely through metabolic overload. We have now uncovered a mitochondrial quality
control pathway that specifically and selectively eliminates mitochondrial carrier proteins in response to
changes in cellular amino acid pools. Removal of these proteins occurs through a selective intermediate
structure called a mitochondrial derived compartment, or MDC. Our current hypothesis is that sequestration of
nutrient carriers by this pathway protects mitochondria in times of cellular metabolic stress. Excitingly, this
pathway appears to be just one wing of what we are proposing is a global cellular system for regulation of
nutrient transporters to control intracellular amino acid levels. In this application, we lay out a long-term goal of
our research program: to ultimately understand how cells regulate metabolite transporters to control cellular
nutrient compartmentalization. As a first step in this process, we will focus on three areas outlined in this
proposal: 1) understanding how mitochondrial nutrient transporters are selectively removed from the
mitochondrial inner membrane for destruction in both yeast and mammals; 2) examining how amino acid levels
trigger this pathway, and 3) investigating the coordination of the mitochondrial MDC pathway with similar
systems that regulate levels of plasma membrane and lysosomal nutrient transporters. Understanding how
intracellular metabolites trigger selective removal and destruction of mitochondrial nutrient carriers will provide
important insights into mechanisms of intra-organelle protein sorting, and identify new modes of cellular
metabolic regulation.

## Key facts

- **NIH application ID:** 9926264
- **Project number:** 5R35GM119694-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Adam Hughes
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926264

## Citation

> US National Institutes of Health, RePORTER application 9926264, Quality Control of Mitochondrial Nutrient Transporters (5R35GM119694-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926264. Licensed CC0.

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