# Mitochondria in the Regulation of Terminal Erythropoiesis

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $522,753

## Abstract

PROJECT SUMMARY/ABSTRACT
The massive daily production of 200 billion red blood cells (RBCs) requires a remarkable coordination of
erythroid cell differentiation and maturation, with processes that are implicated in erythroid enucleation.
Alterations in regulatory mechanisms that control the terminal erythroid cell maturation and enucleation are
implicated in erythroid and other disorders. Limited knowledge of these processes have been an impediment
to therapy interventions and large-scale RBC production. Our long-standing focus on the transcription factor
Foxo3 that is a central regulator of terminal erythropoiesis led us to identifying mitochondria as critical and
dynamic regulators in these processes. We recently showed that mitochondria are actively regulating
erythroid cell enucleation. Notably, we found exogenous pyruvate – a product of glycolysis – but not in situ
produced pyruvate via glycolysis fuel mitochondria and sustains erythroid enucleation suggesting an
unanticipated and significant function for exogenous pyruvate in this process. Our ongoing studies extend
these findings and suggest that ATP-independent mitochondrial functions as well as mitochondrial-related
pathways including clearance may be central to terminal erythropoiesis and their alterations implicated in
disease. Our combined studies raise the possibility that mitochondria might integrate and coordinate several
functions necessary for erythroid cell maturation prior and during enucleation. To further address
mitochondrial functions in terminal erythropoiesis, we will accomplish the following: (Aim 1) we will investigate
the contribution of mitochondrial clearance to erythroid cell maturation vs. enucleation; (Aim 2) we will
investigate the contribution of mitochondrial network and morphology to the regulation of erythroid cell
maturation vs. enucleation, and (Aim 3) we will address the specific pyruvate-mediated pathway that fuel
mitochondria during terminal erythropoiesis. These studies are likely to expose a new mechanism of erythroid
cell maturation and enucleation and to generate critical information for developing new means towards novel
therapies and improving RBC production.

## Key facts

- **NIH application ID:** 10749041
- **Project number:** 5R01HL136255-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SAGHI GHAFFARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $522,753
- **Award type:** 5
- **Project period:** 2017-01-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749041

## Citation

> US National Institutes of Health, RePORTER application 10749041, Mitochondria in the Regulation of Terminal Erythropoiesis (5R01HL136255-06). Retrieved via MORVS 2026-10-03 from https://api.morvs.ai/grant/nih/10749041. Licensed CC0.

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