# Mitochondrial Metabolism and Cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $608,491

## Abstract

PROJECT SUMMARY/ABSTRACT
Transformation of normal cells to cancer cells involves complex changes influenced by oncogenes, inactivation
of tumor suppressors, and disrupted signaling pathways, imposing a metabolic demand that is sustained through
alterations in critical metabolic pathways and the availability of nutrients in the tumor microenvironment to support
tumor expansion. Previously, we have shown that the electron transport chain (ETC) is necessary for in vivo
tumor initiation and progression. However, the exact reasons behind the crucial role of the ETC in tumor growth
remain somewhat unclear. We hypothesize the ETC supports tumor growth by maintaining oxidative tricarboxylic
acid (TCA) cycle activity by replenishing NAD+ and converting succinate to fumarate for production of lipids,
nucleotides, heme, and glutathione. However, a comprehensive understanding of the TCA cycle's importance
in tumor growth has not been achieved thus far. Hence, we chose to focus our investigation on malate
dehydrogenase 2 (MDH2), a key enzyme involved in the final step of the TCA cycle, to explore its significance
in tumor growth. MDH2 has two distinct functions involving conversion of malate to oxaloacetate and cytosolic
NAD+ generation through the malate-aspartate shuttle. Preliminary data, demonstrates that the absence of
MDH2 impaired orthotopic tumor growth of murine lung adenocarcinoma (LUAD) cells in immunocompetent
mice. This proposal outlines our plan to further investigate the necessity of MDH2 in tumor initiation and
progression using a novel MDH2 floxed mouse line with the Kras+/LSL-G12D; Trp53fl/fl (KP) mouse model of LUAD.
Furthermore, as tumors progress, they become hypoxic concomitant with a decline in ETC function and
mitochondria NAD+ regeneration. Moreover, MDH2 plays a role in regenerating cytosolic NAD+. Thus, we will
address whether cytosolic or mitochondrial NAD+ acts as a limiting factor for LUAD in the KP mouse model. To
address this, we have also generated conditional mice expressing cytoplasmic or mitochondrial Lactobacillus
brevis H2O-forming NADH oxidase (LbNOX) enzymes, which convert NADH back to NAD+ in the cytosol or
mitochondria, respectively. To complement these experiments, we will perform CRISPR knockouts of MDH2 or
express CytoLbNOX and MitoLbNOX in orthotopic lung cancer mouse models using mouse cell lines derived
from the KP mouse model. A key set of experiments will assess whether MDH2 is required for normal alveolar
epithelial cell development and function in adult mice. These investigations will enhance our understanding of
the necessity of mitochondrial metabolism dependent TCA cycle and NAD+ regeneration in supporting lung
tumor growth and normal lung epithelial cell function.

## Key facts

- **NIH application ID:** 10994436
- **Project number:** 1R01CA290678-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** NAVDEEP S CHANDEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,491
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994436

## Citation

> US National Institutes of Health, RePORTER application 10994436, Mitochondrial Metabolism and Cancer (1R01CA290678-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994436. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*