Metformin restores mitochondrial bioenergetics and redox homeostasis through modulation of mitochondrial biogenesis and dynamics in patient derived cultured fibroblasts and an animal model of molybdenum cofactor deficiency.

1. Biomed Pharmacother. 2025 Jun;187:118123. doi: 10.1016/j.biopha.2025.118123. Epub 2025 May 5.

Metformin restores mitochondrial bioenergetics and redox homeostasis through modulation of mitochondrial biogenesis and dynamics in patient derived cultured fibroblasts and an animal model of molybdenum cofactor deficiency.

Brondani M(1), Ribeiro RT(1), Pinheiro CV(2), Hoffmann CIH(1), Marcuzzo MB(1), Mohsen AW(3), Wajner M(4), Seminotti B(1), Vockley J(3), Leipnitz G(5).

Author information: (1)Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street-Attached, Porto Alegre, RS 90610-264, Brazil. (2)Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street, Porto Alegre, RS 90035-003, Brazil. (3)Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA. (4)Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street-Attached, Porto Alegre, RS 90610-264, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, RS, Brazil. (5)Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street-Attached, Porto Alegre, RS 90610-264, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street, Porto Alegre, RS 90035-003, Brazil; Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street, Porto Alegre, RS 90610-264, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, 2600 Ramiro Barcelos Street-Attached, Porto Alegre, RS 90610-264, Brazil. Electronic address: guilhian@ufrgs.br.

Molybdenum cofactor deficiency (MoCD) is an inborn error of sulfur metabolism caused by inactivating variants in the genes encoding enzymes of the molybdenum cofactor biosynthetic pathway. Patients present with accumulation of sulfite in the brain with secondary mitochondrial bioenergetics and severe neurological manifestations. To investigate the pathophysiology of this disorder, we evaluated mitochondrial and redox homeostasis in fibroblasts derived from a patient with MoCD type A (MOCS1 deficiency) and in an animal model based on the intracerebroventricular administration of sulfite in Wistar rats. Since treatment for MoCD is largely ineffective, we also investigated the effects of metformin, an antidiabetic drug with neuroprotective potential. Reduced basal, maximal, and ATP-linked respiration and reserve respiratory capacity were verified in MOCS1 deficient fibroblasts. The protein content of MFN1/2, OPA1, DRP1, and NRF1 was also reduced, whereas p-DRP1 (Ser 637) was increased. Superoxide levels were elevated in these cells. Metformin treatment reversed these changes. Further, the p-AMPK/T-AMPK protein ratio and the expression of PRKAA1, PPARGC1A, SIRT1, DNM1L, and mitofusin 1 were increased by metformin in the deficient cells. Sulfite administration into rat brain disturbed the antioxidant defenses, and tricarboxylic acid cycle and electron transfer chain function in the striatum, cerebral cortex and cerebellum. Metformin prevented this bioenergetic dysfunction. Our findings show that metformin elicits positive effects in the brain of sulfite-treated rats and in the MOCS1 deficient cell line by modulating mitochondrial biogenesis and fission, identifying potential therapeutic intervention opportunities in MoCD.

Copyright © 2025 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

DOI: 10.1016/j.biopha.2025.118123 PMID: 40327990 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.