# The Mitochondrial Calcium Uniporter: Implications for NAFLD and Hepatic Insulin Resistance

> **NIH NIH F31** · YALE UNIVERSITY · 2022 · $46,752

## Abstract

Project Summary/Abstract
Type 2 diabetes (T2D) is predicted to impact one third of Americans by the year 2050, yet there are few
treatments available to treat the root cause of insulin resistance: ectopic lipid accumulation. Insufficient
mitochondrial oxidation plays a role in the pathogenesis of T2D and non-alcoholic fatty liver disease (NAFLD);
however, the mechanisms behind this are poorly understood. The calcium-dependent nature of key TCA
enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and isocitrate dehydrogenase) implicate
mitochondrial calcium as a master regulator of mitochondrial metabolism. Additionally, calcium has recently been
implicated as a critical mediator of glucagon-induced alterations in hepatic mitochondrial oxidation. The recent
identification of the mitochondrial calcium uniporter (MCU) has sparked a renewed interest in mitochondrial
calcium signaling, yet a role for MCU in mediating obesity-associated metabolic dysfunction has not been
investigated. Determining the mechanism by which mitochondrial calcium regulates liver physiology and
metabolism is critical to understanding the pathogenesis of NAFLD and hepatic insulin resistance, and has the
potential to identify MCU as a novel drug target.
This work will serve to elucidate the mechanisms by which hepatic MCU regulates mitochondrial metabolism,
and how this contributes to NAFLD and hepatic insulin resistance. The central hypothesis is that MCU plays a
critical role in energy balance by modulating intrahepatic lipolysis and glucagon-induced alterations in hepatic
glucose production and mitochondrial oxidation. This will be addressed using a novel positional isotope NMR
tracer analysis method to directly assess in vivo rates of mitochondrial fluxes.
Taken together, this work will establish the role of MCU in hepatic glucagon signaling and the obesity-associated
mitochondrial dysfunction.

## Key facts

- **NIH application ID:** 10401251
- **Project number:** 5F31DK126362-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Traci Ellen LaMoia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-06-09 → 2024-06-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401251

## Citation

> US National Institutes of Health, RePORTER application 10401251, The Mitochondrial Calcium Uniporter: Implications for NAFLD and Hepatic Insulin Resistance (5F31DK126362-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401251. Licensed CC0.

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