# The Impact of Mitochondrial Pyruvate Carriers on Metabolism and Subcellular Dynamics

> **NIH NIH F30** · PRINCETON UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
 Diabetes mellitus affects over 400 million people worldwide. The majority of this affected population is
diagnosed with type 2 diabetes (T2DM). Recent clinical studies have demonstrated that patients with T2DM
are at higher risk than non-diabetic patients for Parkinson’s disease (PD) and shared subcellular pathologic
features indicate that these disorders have common mechanistic underpinnings. Clinical trials have begun to
investigate the therapeutic benefit of various T2DM treatments in the context of PD. A new generation of
insulin sensitizers engineered to inhibit mitochondrial pyruvate carriers (MPCs) has shown therapeutic promise
in experimental models of T2DM and PD. As MPCs are a drug target in the treatment of both disorders, further
study of these transmembrane proteins could uncover a mechanistic link between T2DM and PD. MPCs are
highly conserved between yeast and humans and therefore this study proposes to take advantage of the
simplicity and genetic malleability of the model organism Saccharomyces cerevisiae. This project will provide a
deeper understanding of the role of MPCs in regulating cellular metabolism, organelle dynamics, and
mitophagy. My first aim will investigate the hypothesis that MPCs are responsible for the transport of branched-
chain amino acid (BCAA) metabolites, specifically α-ketoisovalerate (KIV). To achieve this goal I will first
engineer yeast strains with altered MPC monomer expression. Isolated mitochondria from these strains will be
subjected to biochemical assays and gas chromatography instrumentation will be used to determine the
resulting substrate and product concentrations. The second hypothesis investigated by this study is that the
lack of functional MPCs will increase mitochondrial tethering to the endoplasmic reticulum and vacuole within
yeast. To evaluate intracellular organelle dynamics and morphology I will employ fluorescent reporters and
microscopy techniques. The third aim will explore the hypothesis that MPC inhibition decreases mitochondrial
recycling and ATP production. Mitochondrial degradation and ATP production will be investigated by employing
imaging, immunoblotting, and respiration assays. This project will clarify the downstream effects of MPC
inhibition, thereby helping to uncover the molecular basis for the link between T2DM and PD. By providing a
better understanding of the impact of MPC inhibition on cellular metabolism, organelle dynamics, and
mitochondrial function, this study will inform the development of novel therapeutics for both disorders. The
proposed research project will be conducted at Princeton University under the guidance of a superbly suited
team of mentors (Sponsor: Dr. José Avalos, Co-sponsor: Dr. Coleen Murphy, Collaborators: Dr. Clifford
Brangwynne and Dr. Daniel Cohen). The enclosed proposal contains a training plan to improve knowledge of
scientific techniques, enhance critical thinking, and refine communication of scientific material. Addi...

## Key facts

- **NIH application ID:** 10067396
- **Project number:** 1F30GM139398-01
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Therese Kichuk
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067396

## Citation

> US National Institutes of Health, RePORTER application 10067396, The Impact of Mitochondrial Pyruvate Carriers on Metabolism and Subcellular Dynamics (1F30GM139398-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10067396. Licensed CC0.

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