Secondary Mitochondrial Dysfunction in Gaucher Disease Type I, II and III—Review of the Experimental and Clinical Evidence

Dewsbury, M, Purcell, T, Hughes, D ORCID: 0000-0003-4531-9173, Donald, A, Hargreaves, IP ORCID: 0000-0002-2760-5603 and Stepien, KM ORCID: 0000-0003-0148-6332 (2025) Secondary Mitochondrial Dysfunction in Gaucher Disease Type I, II and III—Review of the Experimental and Clinical Evidence. Genes, 16 (11). p. 1269. ISSN 2073-4425

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Abstract

Gaucher disease (GD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The pathogenic defects result in a misfolded protein, which can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The reduced enzyme activity leads to accumulation of its substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), within lysosomes or macrophages and with prominent disease manifestations in reticuloendothelial tissues such as liver, spleen and bone marrow. GCase defects alter both the mitochondria and the lysosome. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby activating α-synuclein accumulation. GCase can also be imported into the mitochondria, where it fosters the integrity and function of mitochondrial respiratory chain (MRC) complex I. Thus, the reduced GCase activity impairs the normal mitochondrial function and increases oxidative stress in this organelle, which may contribute to cell death. However, further studies are required to confirm this mechanism of MRC dysfunction. In this review we have systematically evaluated the evidence for oxidative stress in individuals affected by GD, as well as the currently available therapies and adjunctive therapies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for GD.

Item Type:	Article
Uncontrolled Keywords:	0604 Genetics; 3105 Genetics
Subjects:	R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	MDPI
Date of acceptance:	15 October 2025
Date of first compliant Open Access:	30 October 2025
Date Deposited:	30 Oct 2025 10:22
Last Modified:	30 Oct 2025 10:30
DOI or ID number:	10.3390/genes16111269
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27448

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