# The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $343,895

## Abstract

Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide and results in health
care costs of at least $2.4 billion per year in the United States alone.1 It is caused by a mutation in the β -globin gene
which leads to the formation of hemoglobin S (HbS). HbS is able to polymerize and leads to 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 ROS accumulation triggers a cascade of oxidative reactions that damage lipids, 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:** 10626863
- **Project number:** 5R01HL136622-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Angela Rivers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $343,895
- **Award type:** 5
- **Project period:** 2020-12-08 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626863

## Citation

> US National Institutes of Health, RePORTER application 10626863, The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease (5R01HL136622-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10626863. Licensed CC0.

---

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