# The Role of NDUFA4L2 in Clear Cell Renal Cell Carcinoma

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $9,840

## Abstract

ABSTRACT
 Kidney cancer is one of the ten most common cancers in the US and accounts for over 100,000 deaths each
year. Over 80% of kidney cancers are classified as clear cell renal cell carcinoma (ccRCC), and insight as to
how this disease develops is scarce. One characteristic of ccRCC is the overexpression of NADH
dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2), which is overexpressed in over 90%
of ccRCC patients. Additionally, NDUFA4L2 is necessary for cell proliferation and survival, therefore
indicating its importance in the development of ccRCC. However, the function of NDUFA4L2 has yet to be
elucidated. Previous studies have shown that NDUFA4L2 plays a role in the switch from mitochondrial
oxidative phosphorylation to glycolysis, a metabolic shift that is observed in ccRCC. Additional studies
suggested that NDUFA4L2 may be implicated in the inhibition of mitochondrial complex I activity. However,
this proposed function has yet to be investigated in ccRCC. Functional studies on NDUFA4L2 in vivo are
lacking due to the prenatal lethality of NDUFA4L2 knockout mice. The Gudas lab has generated a
TRAnsgenic Cancer of the Kidney (TRACK) murine model in which NDUFA4L2 is overexpressed.
Additionally, this novel murine model recapitulates the human ccRCC disease, as demonstrated by genome-
wide profiling of the TRACK kidneys. Previous collaborative work between the Gudas lab and the Heller lab
showed that mesoscale nanoparticles (MNPs) localize in the mouse kidneys up to 25 times more than they do
in other organs. Furthermore, these MNPs localized more in the “clear” cells, or lipid-filled cells, of the
TRACK kidneys relative to normal proximal tubule cells. Consequently, these MNPs present a novel method
of delivering drugs, therapeutics, or other investigative tools to the site of disease in the renal carcinogenesis
murine model. We therefore aim to utilize this innovative approach to investigate the function of NDUFA4L2
in ccRCC. Through the utilization of the TRACK mouse model and the kidney-targeting MNPs, we will: 1)
elucidate the role of NDUFA4L2 on mitochondrial function, and 2) determine the knockdown efficacy of
siNDUFA4L2-encapsulating MNPs in TRACK mice. In order to investigate the mitochondrial function of
NDUFA4L2, we will analyze mitochondrial function, ATP production, ROS levels, and complex I activity in
cultured human ccRCC cells and TRACK mice. MNPs encapsulating siRNA specific for NDUFA4L2 will then
be injected into TRACK mice to investigate whether NDUFA4L2 knockdown can be successfully achieved
using this novel method. The proposed studies will delineate the functions of NDUFA4L2 in ccRCC and
elucidate a possible delivery method of NDUFA4L2 knockdown specific to the kidneys. Findings from this
proposal will provide critical insight into the underlying processes of ccRCC and present potential therapeutic
strategies.

## Key facts

- **NIH application ID:** 10218022
- **Project number:** 5F31CA213814-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jaclyn Kubala
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $9,840
- **Award type:** 5
- **Project period:** 2017-07-01 → 2020-10-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218022

## Citation

> US National Institutes of Health, RePORTER application 10218022, The Role of NDUFA4L2 in Clear Cell Renal Cell Carcinoma (5F31CA213814-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10218022. Licensed CC0.

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