# Mitochondrial NAD+ in Acute Myeloid Leukemias

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $496,412

## Abstract

PROJECT SUMMARY
 Targeting mitochondrial metabolism is an active area of research in Acute Myeloid Leukemia (AML).
The cumulative data indicate that AML cells have heightened mitochondrial activity and prefer glutamine as a
carbon source compared to noncancerous cells. Nevertheless, a challenge that emerges when trying to target
these vulnerabilities one at a time is the continued presence of treatment-refractory AML cells, which ultimately
result in relapse or developed resistance. The likely causes are the adaptable nature of metabolic pathways
and cell-to-cell variability, either due to local environment or genetics.
 We propose that loss of mitochondrial nicotinamide adenine dinucleotide (NAD+) will simultaneously
block multiple metabolic pathways used by AML with minimal toxicity in healthy cells. We recently published
that the SLC25A51 transporter is a critical regulator of mitochondrial NAD+ levels in human cells. SLC25A51 is
directly responsible for NAD+ import, and modulation of SLC25A51 expression controls the concentrations of
NAD+ in the mitochondrial matrix. Loss of SLC25A51 resulted in depleted NAD+ only in mitochondria and not
throughout the whole cell. Until now, there has been no way to selectively deplete mitochondrial NAD+ through
an endogenous target. Notably, we have found a broad vulnerability across AML cells to SLC25A51 depletion,
including lines that previously were found to escape Complex I inhibition.
 This proposal will determine the extent that SLC25A51 impacts AML in vivo, elucidate the pathways
that this transporter supports, and determine the molecular mechanisms controlling its expression. As there are
limited treatment options for patients, the long-term benefit of this work is to establish a rationale for targeting
mitochondrial NAD+ through SLC25A51 and to identify additional AML therapeutic approaches.

## Key facts

- **NIH application ID:** 10913369
- **Project number:** 5R01CA272490-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Xiaolu Ang Cambronne
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,412
- **Award type:** 5
- **Project period:** 2023-08-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913369

## Citation

> US National Institutes of Health, RePORTER application 10913369, Mitochondrial NAD+ in Acute Myeloid Leukemias (5R01CA272490-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10913369. Licensed CC0.

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