# Understanding the molecular alterations of diseases due to SLC25A1 deficiency

> **NIH NIH R21** · GEORGETOWN UNIVERSITY · 2020 · $194,375

## Abstract

The citrate carrier, Slc25a1, is a nuclear encoded protein that localizes in the inner mitochondrial
membrane, where it serves an important function in promoting the flux of the lipid precursor citrate in the
cytoplasm. Slc25a1 gene alterations play a key role in the pathogenesis of a variety of developmental
disorders. Heterozygous deletions of the gene are hallmark DiGeorge and Velo-Cardio-Facial Syndrome,
while missense Slc25a1 gene mutations give raise to combined D-2-/L-2-hydroxyglutaric aciduria and to a
variety of still incompletely classified disorders. The clinical spectrum of manifestations associated with
Slc25a1 dysfunction consists of severe craniofacial abnormalities, brain abnormalities, respiratory
insufficiency, epileptic encephalopathy, as well as metabolic dysfunction characterized by lactic acidosis
and by urinary excretion of two abnormal products of the tricyclic acid (TCA) cycle, D2-L2 hydroxyglutaric
acids. The severity of manifestations seen in patients harboring Slc25a1 mutations is variable, spanning
from very moderate to extremely severe, leading to early death within the first month of age.
Unfortunately, there is no therapy for syndromes associated with Slc25a1 deficiency, due to the lack of full
understanding of the exact molecular mechanisms by which Slc25a1 operates. To address this gap in
knowledge we have developed the first murine and zebrafish models of Slc25a1 deficiency and we find that
in both systems Slc25a1 loss results in pre- and perinatal lethality and in pathologic features that
recapitulate salient aspects of human Slc25a1 deficiency. We further identify and novel activity of Slc25a1
consisting in regulation of mtDNA homeostasis. Molecular and metabolic analyses demonstrate that
tissues and cells derived from Slc25a1-/- mice exhibit abnormal TCA cycle flux, respiratory deficit and
upregulation of several metabolic pathways, including lipid synthetic pathways. This suggests that the
pathogenesis of Slc25a1 disorders may be due to harmful upregulation of compensatory metabolic routes,
at least in part consequent to mitochondrial dysfunction. We propose to test this idea with two specific
aims. In Aim 1 we will map the metabolic and molecular changes due to Slc25a1 deficiency and we will
define the mechanisms by which Slc25a1 affects mitochondrial activity. In Aim 2 we will compare the
effects of Slc25a1 loss versus human-associated Slc25a1 mutations in the model organism zebrafish.
These studies will be pivotal for the identification of the molecular alterations associated with Slc25a1
dysfunction which, in turn, could strategically guide future therapeutic efforts.

## Key facts

- **NIH application ID:** 9881263
- **Project number:** 5R21DE028670-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** MARIA L AVANTAGGIATI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881263

## Citation

> US National Institutes of Health, RePORTER application 9881263, Understanding the molecular alterations of diseases due to SLC25A1 deficiency (5R21DE028670-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881263. Licensed CC0.

---

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