# Ethanol and aldehyde dehydrogenases in health and disease

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $597,859

## Abstract

Acetaldehyde, a toxic metabolite of ethanol, contributes to many human pathologies. It is mainly detoxified by
the mitochondrial aldehyde dehydrogenase 2 (ALDH2). In addition to the common ALDH2*2 of >500 million
people of East Asian ancestry, we have identified additional common ALDH2 variants of other genetic
ancestries. Ethanol exposure in cells expressing these less active ALDH2 variants increases aldehydic load,
mitochondrial dysfunction, and cell death. Considering the critical role of aldehydes on health, that ethanol (via
fermentation) was present throughout mammalian evolution, and that ALDH2 insufficiencies are common, we
hypothesize that enzymes other than ALDH2 may provide an additional detoxification capacity against increased
aldehydic load and the resulting cytotoxicity. We also hypothesize that inactive variants of these other enzymes
may be common in specific genetic ancestry, rendering individuals who have ALDH2 insufficiency even more
sensitive to ethanol-induced toxicity than carriers of ALDH2 insufficiency alone. If these hypotheses are correct,
the assessment of ALDH2 genetic polymorphisms alone is not sufficient to assess disease risk.
In this proposal, we focus on mitochondrial enzymes because of the central role of mitochondrial dysfunction in
many human pathologies. Our specific aims for the project are:
Aim 1: Identify variants common to specific ancestry groups of aldehyde metabolizing mitochondrial enzymes
and determine whether they have reduced activity or stability in vitro
Aim 2: Determine if inactive variants of these mitochondrial enzymes alone or together with ALDH2*2 (as a
model of ALDH2 insufficiency) affect ethanol-induced mitochondrial dysfunction and inflammation in culture.
Aim 3: Determine the impact of acute and chronic ethanol treatment, in vivo, in mice in which an inactive human
ALDH2 variant and an inactive human variant of a second enzyme identified in Aim 2 were knocked in.
Innovation: our work represents the first systematic study to begin identifying additional mitochondrial enzymes
that complement ALDH2 in reducing ethanol- and aldehydes-induced toxicity. Our study is also the first to
examine the potential risk from ethanol exposure in different human genetic ancestry using model systems.
Significance: As ethanol is consumed by most adults in the world, if our hypotheses are correct that additional
mitochondrial enzymes are critical in protecting from an increased mitochondrial aldehydic load, this study will
have important clinical implications and may further contribute to precision medicine based on the activity of
these understudied mitochondrial enzymes.

## Key facts

- **NIH application ID:** 10978572
- **Project number:** 2R01AA011147-28
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** DARIA MOCHLY-ROSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,859
- **Award type:** 2
- **Project period:** 1996-09-30 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978572

## Citation

> US National Institutes of Health, RePORTER application 10978572, Ethanol and aldehyde dehydrogenases in health and disease (2R01AA011147-28). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10978572. Licensed CC0.

---

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