3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum–Mitochondria Crosstalk in Rat Brain

  • Mateus Struecker da Rosa
  • Nevton Teixeira da Rosa-Junior
  • Belisa Parmeggiani
  • Nícolas Manzke Glänzel
  • Leonardo de Moura Alvorcem
  • Rafael Teixeira Ribeiro
  • Mateus Grings
  • Moacir Wajner
  • Guilhian LeipnitzEmail author
Original Article


3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a neurometabolic disorder characterized by predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in tissues and biological fluids. Patients often present in the first year of life with metabolic acidosis, non-ketotic hypoglycemia, hypotonia, lethargy, and coma. Since neurological symptoms may be triggered or worsened during episodes of metabolic decompensation, which are characterized by high urinary excretion of organic acids, this study investigated the effects of HMG intracerebroventricular administration on redox homeostasis, citric acid cycle enzyme activities, dynamics (mitochondrial fusion and fission), and endoplasmic reticulum (ER)–mitochondria crosstalk in the brain of neonatal rats euthanized 1 (short term) or 20 days (long term) after injection. HMG induced lipid peroxidation and decreased the activities of glutathione peroxidase (GPx) and citric acid cycle enzymes, suggesting bioenergetic and redox disruption, 1 day after administration. Levels of VDAC1, Grp75, and mitofusin-1, proteins involved in ER-mitochondria crosstalk and mitochondrial fusion, were increased by HMG. Furthermore, HMG diminished synaptophysin levels and tau phosphorylation, and increased active caspase-3 content, indicative of cell damage. Finally, HMG decreased GPx activity and synaptophysin levels, and changed MAPK phosphorylation 20 days after injection, suggesting that long-term toxicity is further induced by this organic acid. Taken together, these data show that HMG induces oxidative stress and disrupts bioenergetics, dynamics, ER-mitochondria communication, and signaling pathways in the brain of rats soon after birth. It may be presumed that these mechanisms underlie the onset and progression of symptoms during decompensation occurring in HL-deficient patients during the neonatal period.


3-Hydroxy-3-methyglutaric acid Redox and energy homeostasis Mitochondrial dynamics Endoplasmic reticulum-mitochondria crosstalk Cerebral cortex 


Funding Information

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Rede Instituto Brasileiro de Neurociência (IBN-Net), and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN).

Compliance with Ethical Standards

The experiments were approved by the local Animal Ethics Commission from Universidade Federal do Rio Grande do Sul, and according to the National Animal Rights Regulations (Law 11.794/ 2008).

Conflict of Interest

The authors declare that they have no conflicts of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mateus Struecker da Rosa
    • 1
  • Nevton Teixeira da Rosa-Junior
    • 1
  • Belisa Parmeggiani
    • 1
  • Nícolas Manzke Glänzel
    • 1
  • Leonardo de Moura Alvorcem
    • 1
  • Rafael Teixeira Ribeiro
    • 1
  • Mateus Grings
    • 1
  • Moacir Wajner
    • 2
    • 3
  • Guilhian Leipnitz
    • 2
    • 4
    Email author
  1. 1.Programa de Pós-Graduação em Ciências Biológicas: BioquímicaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  4. 4.Programa de Pós-Graduação em Fisiologia, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil

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