# NAD(P)H quinone oxidoreductase 1 (NQO1)-mediated bypass of mitochondrial electron transport chain with artificial and endogenous substrates

> **NIH NIH R21** · SCINTILLON INSTITUTE FOR PHOTOBIOLOGY · 2023 · $529,650

## Abstract

Abstract
A wide range of rare and common diseases are linked to mitochondrial dysfunction and associated redox
imbalance. Restoration of the underlying redox imbalance by decreasing the cellular NADH/NAD+ ratio could be
seen as an extremely useful generalizable strategy in the context of multiple disease states. NAD(P)H:quinone
oxidoreductase 1 (NQO1) is a soluble cytoplasmic enzyme that has been mostly viewed as a xenobiotic-
metabolizing enzyme, or a bioactivator of cancer drugs at the expense of reducing equivalents of NAD(P)H.
Interestingly, some of NQO1 artificial substrates, mostly naphthoquinones, when reduced are capable of
subsequently donating their electrons to the mitochondrial electron transport chain downstream of Complex I.
This NQO1-mediated alternative electron transfer is therefore an attractive strategy to alleviate reductive stress
and support ATP homeostasis as it depends on an endogenous enzyme and only requires addition of respective
naphthoquinones. However, naphthoquinones capable of being reduced by NQO1 are either natural products or
synthetic redox scaffolds (e.g. idebenone), and we currently lack information on endogenous substrates of NQO1
and its place in cellular redox metabolism. To close this knowledge gap, we will use activity-based metabolomic
profiling with recombinant NQO1 to identify cellular endogenous metabolites that are interconverted by this
enzyme. Next, we will reconstitute the NQO1-mediated electron transfer with various naphthoquinones in
isolated mitochondria and will study the bioenergetics of this non-canonical point of entry of reducing equivalents.
This will allow us to rigorously characterize naphthoquinones and related redox-active molecules for their ability
to safely bypass a corrupted mitochondrial electron transport chain without inducing oxidative stress. Our current
approach will, for the first time, allow us to identify physiological NQO1 substrates and help us better reconstruct
the NQO1-mediated electron transfer. This work will ultimately pave the way for developing therapeutic
modalities that are based on redox-active small molecules that can alleviate reductive stress.

## Key facts

- **NIH application ID:** 10789749
- **Project number:** 1R21AG085012-01
- **Recipient organization:** SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
- **Principal Investigator:** Valentin Cracan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $529,650
- **Award type:** 1
- **Project period:** 2023-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789749

## Citation

> US National Institutes of Health, RePORTER application 10789749, NAD(P)H quinone oxidoreductase 1 (NQO1)-mediated bypass of mitochondrial electron transport chain with artificial and endogenous substrates (1R21AG085012-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10789749. Licensed CC0.

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