# Diversity Supplement - The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $86,023

## Abstract

Parent Grant Abstract
Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide and results in
healthcare costs of at least $2.4 billion per year in the United States alone.1–3 It is caused by a mutation in the
β-globin gene which leads to the formation of hemoglobin S (HbS). HbS polymerizes when deoxygenated and
leads to red blood cell (RBC) sickling, hemolysis, acute and chronic pain, chronic hemolytic anemia,
multisystem organ damage, and a much-shortened life expectancy. Novel targeted therapeutic approaches are
essential to overcome the cascade of the events that begin with HbS polymerization. Recently many
investigators have demonstrated that SCD organ pathology is associated with oxidative stress. Oxidative
stress occurs when there is an increase in oxidants without a similar increase in antioxidants.
Excessive reactive oxygen species (ROS) accumulation triggers a cascade of oxidative reactions that damage
lipids and proteins of red blood cells ultimately leading to hemolysis or early destruction. Although much
progress has been made to ROS mediated complications in SCD patients, further studies are essential in an
attempt to understand the source of ROS and factors involved in HbS polymerization and hemolytic process.
We have demonstrated in our laboratory that SCD RBCs retain mitochondria. In addition, we have shown that
these retained mitochondria create excessive intracellular ROS generation and are associated with hemolysis.
Our preliminary data also show that these mitochondria cause an increased oxygen consumption in the red
blood cells. We hypothesize that erythrocyte mitochondrial retention causes exacerbation of SCD
pathogenesis by two non-mutually exclusive mechanisms 1) Mitochondria generate excessive ROS leading to
hemolysis and 2) Mitochondria increased oxygen consumption leading to a hypoxic intracellular environment
that causes Hb S polymerization. An understanding of mitochondrial oxygen consumption and consequential
oxidative stress in the pathogenesis of SCD represents a novel opportunity for the development of targeted
therapeutic agents. The possibility of mitochondria derived ROS generation and oxygen consumption in RBCs
are novel targets that have not been investigated before. Our long-term goal is to translate the novel finding
of mitochondria-retaining SCD RBCs into new pharmaceutical therapies for sickle cell disease.

## Key facts

- **NIH application ID:** 10557738
- **Project number:** 3R01HL136622-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Angela Rivers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $86,023
- **Award type:** 3
- **Project period:** 2020-12-08 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10557738

## Citation

> US National Institutes of Health, RePORTER application 10557738, Diversity Supplement - The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease (3R01HL136622-04S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10557738. Licensed CC0.

---

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