# Investigating the Mitochondrial-Derived Compartment Pathway

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondria are central hubs of cellular metabolism, and their dysfunction is linked to a host of age-related and
metabolic disorders. As a major source of cellular energy production and metabolite biosynthesis, mitochondria
continually take up and release a variety of intracellular nutrients. This renders mitochondria vulnerable to
changes in nutrient concentrations frequently observed in disorders associated with metabolic overload. Indeed,
recent work from our lab showed that mitochondria are uniquely sensitive to elevations in intracellular amino acid
load, and that amino acid toxicity is a key driver of age-related mitochondrial decline. Moving forward, a major
goal of our lab is to understand mechanisms by which elevated amino acids impair mitochondrial function, and
identify pathways that protect mitochondria from amino acid stress. In work during the last project period, we
identified a key role for the amino acid cysteine in regulating mitochondrial respiration, and uncovered a new
cellular structure, called the Mitochondrial-Derived Compartment (MDC), that protects cells from harmful effects
of excess amino acids. Our current data suggests that MDCs are dynamic, organelle-like structures that are
generated from mitochondria in response to intracellular amino acid elevation. Upon formation, MDCs selectively
sort and remove proteins of the mitochondrial carrier superfamily, key mediators of metabolite transport across
the mitochondrial inner membrane, away from the rest of the mitochondrial network. MDCs are conserved from
yeast to humans, and loss of the MDC pathway renders cells susceptible to amino acid overload. These results
have led to our current working model that MDC formation represents a new mechanism to acutely regulate
mitochondrial nutrient transporters in response to changes in cellular metabolic supply. Currently, our
understanding of the biogenesis, nutrient regulation, and role of MDCs in cellular metabolism is far from complete.
During the next project period, we will work in both yeast and mammalian systems to elucidate mechanisms and
machinery involved in MDC biogenesis, identify nutrient cues and sensors that control MDC activation, and
determine the role of this pathway in mitochondrial and cellular metabolism. Because mitochondrial metabolite
transporters are key regulatory points of cellular metabolism, we anticipate that elucidating the function of this
new cellular pathway will have significant impact on our understanding of mitochondrial physiology and its role
in human disease.

## Key facts

- **NIH application ID:** 10207158
- **Project number:** 2R35GM119694-06
- **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:** 2021
- **Award amount:** $381,250
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207158

## Citation

> US National Institutes of Health, RePORTER application 10207158, Investigating the Mitochondrial-Derived Compartment Pathway (2R35GM119694-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10207158. Licensed CC0.

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