# Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $351,000

## Abstract

Project Summary
Alcoholic liver disease (ALD) causes 48% of cirrhotic deaths derived from hepatitis. Increased reactive oxygen
species (ROS) production is a major pathogenic factor leading the progression of ALD from steatosis to alcoholic
hepatitis (AH). However, clinical trials testing compounds that unselectively scavenge ROS or enhance
acquainted antioxidants were unsuccessful. This lack of success supports that ALD disrupts endogenous
antioxidant systems inside mitochondria, an organelle formed by two membranes that limit the entry and action
of the compounds tested. Our proposal stems from our identification of a mitochondrial antioxidant and redox
system impaired in ALD and previously unknown in liver. This system is constituted by the mitochondrial inner
membrane ATP binding cassette transporter ABCB10, which exports a previously unknown cargo through its
ATP hydrolysis activity (ATPase). Our preliminary data supports that ABCB10 decreases ALD severity by
decreasing ROS-mediated damage, as liver-specific deletion of ABCB10 exacerbates hepatic oxidative damage
and ALD severity in mice. We hypothesize that ABCB10 transport activity protects from ALD by limiting
EtOH-induced oxidative damage. Remarkably, our new data shows that ABCB10 content is decreased in late-
stage ALD, including mice and humans with AH. Mechanistically, we show for the first time that ABCB10 exports
Biliverdin (BV) from the mitochondrial matrix to the cytosol, where biliverdin reductase (BLVR) is located.
Exported BV is used by cytosolic BLVR to regenerate intracellular Bilirubin (BR) destined for ROS scavenging.
We hypothesize that ABCB10-mediated BV export is decreased in ALD, shrinking the intrahepatocyte
BR pool that protects from ROS-mediated damage. Accordingly, our data show that: i) EtOH and ABCB10
deletion reduce intrahepatocyte BR levels and ii) ABCB10 deletion causes mitochondrial BV accumulation and
increases intracellular ROS levels. Thus, we will: 1) Determine the role of ABCB10 in ALD in vivo and 2)
Determine the mechanism by which ABCB10 modulates oxidative stress in ALD.

## Key facts

- **NIH application ID:** 10201420
- **Project number:** 5R01AA026914-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Orian S Shirihai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201420

## Citation

> US National Institutes of Health, RePORTER application 10201420, Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease (5R01AA026914-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201420. Licensed CC0.

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