# Mitochondrial BCAA transporter in physiology and disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $455,000

## Abstract

PROJECT SUMMARY
Emerging evidence suggests that brown adipose tissue (BAT) functions as a significant metabolic-sink for
glucose and fatty acids, but also branched-chain amino acids (BCAA; valine, leucine, and isoleucine). Our recent
study shows that cold-activated BCAA catabolism in the BAT promotes systemic BCAA clearance in mice and
humans, and that this metabolic-sink action is tightly coupled with its ability to improve glucose tolerance and
insulin sensitivity.
The notion of BAT being a metabolic-sink for BCAA provides new insights into the epidemiological observations
that increased circulating BCAA levels are associated with insulin resistance and type 2 diabetes, conditions
under which BAT mass/activity is reduced. However, the mechanisms remain insufficiently understood because
the gatekeeper of mitochondrial BCAA transport, i.e., mitochondrial BCAA transporter that determines BCAA
fate in the mitochondria vs. cytosol, was unknown for many years.
We recently identified the first mitochondrial BCAA transporter, SLC25A44, in mammals. Our preliminary data
suggest that SLC25A44 is required for mitochondria BCAA oxidation, BAT thermogenesis, and systemic glucose
homeostasis. Accordingly, this proposal aims to determine the mechanisms by which SLC25A44 loss causes
systemic glucose intolerance and insulin resistance. First, we will determine the metabolic organ that is primarily
responsible for the diabetic phenotype through characterization of the newly developed BAT-specific SLC25A44
deficient mice. Second, we will employ metabolomics and biochemical approaches to determine the molecular
mechanisms by which SLC25A44 loss alters mitochondrial function and intracellular signaling pathways. Lastly,
we aim to examine the regulatory mechanisms of SLC25A44 expression and function. The work resulting from
this application will establish a conceptual framework to understand the regulation of intracellular BCAA fate,
and also provide a new roadmap to reverse disease phenotypes that stem from dysregulation in the BCAA
catabolic processes.

## Key facts

- **NIH application ID:** 10318672
- **Project number:** 5R01DK125283-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Shingo Kajimura
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $455,000
- **Award type:** 5
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318672

## Citation

> US National Institutes of Health, RePORTER application 10318672, Mitochondrial BCAA transporter in physiology and disease (5R01DK125283-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10318672. Licensed CC0.

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