In vivo evidence that bezafibrate prevents oxidative stress and mitochondrial dysfunction caused by 3-methylglutaric acid in rat liver.

Abstract

High urinary excretion and tissue accumulation of 3-methylglutaric acid (MGA) are observed in patients affected by 3-hydroxy-3-methylglutaric (HMGA) and 3-methylglutaconic (MGTA) acidurias. The pathomechanisms underlying the hepatic dysfunction commonly observed in these disorders are not fully elucidated so that we investigated here the effects of intraperitoneal administration of MGA on redox homeostasis, mitochondrial bioenergetics, biogenesis and dynamics in rat liver. The effects of a pre-treatment with the protective compound bezafibrate (BEZ) were also determined. Our data showed that MGA induced lipid peroxidation and altered enzymatic and non-enzymatic antioxidant defenses in liver, indicating redox homeostasis disruption. BEZ prevented most of these alterations induced by MGA. MGA also decreased the activities of the respiratory chain complexes II and IV and increased of II-III, whereas BEZ prevented the alteration in complex II activity. Furthermore, MGA decreased levels of nuclear PGC-1α and Sirt1, and increased levels of AMPKα1 and cytosolic PPARγ, which were blocked by BEZ. MGA augmented the levels of mitofusin-1 and dynamin-related protein 1, suggesting that both fusion and fission mitochondrial processes are enhanced by MGA. BEZ was able to prevent only the changes in mitofusin-1 levels. Collectively, these findings indicate that oxidative stress and mitochondrial dysfunction are mechanisms involved in the hepatic dysfunction found in HMGA and MGTA. It is also presumed that mitochondrial biogenesis stimulation may constitute an attractive approach to reduce MGA toxicity in liver of individuals affected by HMGA and MGTA.

• Authors: Nevton Teixeira da Rosa-Junior, Belisa Parmeggiani, Nícolas Manzke Glänzel, Leonardo de Moura Alvorcem, Marina Rocha Frusciante, Carlos Severo Dutra Filho, Moacir Wajner, Guilhian Leipnitz
• Journal: Biochimie (Biochimie) 2020 Apr - May Vol. 171-172 Pg. 187-196 ISSN: 1638-6183 [Electronic] France
• PMID: 32169667 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• Antioxidants
• Glutarates
• 3-methylglutaric acid
• 3-methylglutaconic acid
• Meglutol
• Bezafibrate

Topics

• Animals
• Antioxidants (therapeutic use)
• Bezafibrate (therapeutic use)
• Chemical and Drug Induced Liver Injury (drug therapy, metabolism)
• Female
• Glutarates (toxicity)
• Lipid Peroxidation
• Liver (metabolism)
• Male
• Meglutol (analogs & derivatives, metabolism, toxicity)
• Mitochondria (metabolism)
• Organelle Biogenesis
• Oxidative Stress (drug effects)
• Rats
• Rats, Wistar