# Characterizing the biological function and therapeutic potential of mitochondrial NADP(H)

> **NIH NIH K99** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $119,836

## Abstract

PROJECT SUMMARY/ABSTRACT
Cancer cell proliferation requires a coordinated metabolic network that supports biomass accumulation and
maintains cellular redox homeostasis. An essential mechanism that cancer cells rely on to achieve coordinated
anabolic cell growth with redox balance is the inter-conversion of nicotinamide adenine dinucleotide phosphate
between the oxidized (NADP+) and reduced (NADPH) forms (the total of NADP+ and NADPH is referred to as
NADP(H) hereafter). Because NADP(H) molecules cannot cross membrane structures, cellular NADP(H) pools
are compartmentalized. In the cytosol, NADPH acts as a cofactor for fatty acid biosynthesis, and as the
reducing power for glutathione regeneration and anti-oxidant defense. Mitochondria are central organelles of
cellular metabolism that participate in a number of biosynthetic pathways as well as redox regulation. However,
the role of the mitochondrial NADP(H) pool in supporting cell proliferation remains to be elucidated.
My preliminary results indicate that mitochondrial NADP(H) is not required for anti-oxidant defense as currently
thought. Instead, its main function is to support de novo proline synthesis required to maintain cell proliferation.
Cancer cell growth is stalled upon depletion of the mitochondrial NADP(H) pool. Supplementing exogenous
proline is both necessary and sufficient to restore cell growth. The proposal is designed to further strengthen
these observations by defining the mechanistic basis of how mitochondrial NADP(H) availability specifically
determines proline synthesis, and to determine contexts in which targeting the mitochondrial NADP(H) pool is
beneficial for cancer treatment. The following Specific Aims are pursued in this application: Aim 1. Investigate
the function of the mitochondrial NADP(H) pool in supporting cancer cell growth (K99); Aim 2. Identify the
molecular mechanisms whereby mitochondrial NADP(H) availability dictates proline biosynthesis (K99); Aim 3.
Examine the vulnerability of cancer cells with isocitrate dehydrogenase 2 (IDH2) mutations by targeting
mitochondrial NADP(H) (R00). The knowledge and scientific expertise that I acquire from these studies and
throughout the award period will also facilitate my transition into the future independent career, with the long-
term goal to study the mechanistic basis of cancer and develop clinical approaches for cancer treatment.
In addition to the scientific goals, I have also outlined a detailed career development plan in this application in
order to obtain skills that are important for leading an independent research laboratory. I will conduct the
proposed research and carry out the training plan under the mentorship of Dr. Craig Thompson. I will embark
on the academic environment provided by Memorial Sloan-Kettering Cancer Center to achieve these goals and
transition to a position as an independent principle investigator of cancer biology.

## Key facts

- **NIH application ID:** 10128416
- **Project number:** 5K99CA248711-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Jiajun Zhu
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $119,836
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-04-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128416

## Citation

> US National Institutes of Health, RePORTER application 10128416, Characterizing the biological function and therapeutic potential of mitochondrial NADP(H) (5K99CA248711-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128416. Licensed CC0.

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