Metabolic studies of a patient harbouring a novel S487L mutation in the catalytic subunit of AMPK

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Arita, Juliana Harumi ; Barros, Mario H. ; Ravagnani, Felipe Gustavo ; Ziosi, Marcello ; Sanches, Livia Rentas ; Picosse, Fabiola Rosa ; Lopes, Tania Oliveira ; Aguiar, Patricia de Carvalho ; Macabelli, Carolina Habermann ; Chiaratti, Marcos R. ; Pedroso, Jose Luiz ; Quinzii, Catarina M. ; Povoas Barsottini, Orlando Graziani ; Ferreiro-Barros, Claudia Cristina

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE; v. 1864, n. 5, p. 8-pg., 2018-05-01.

Abstract

AMP-activated protein kinase (AMPK) regulates many different metabolic pathways in eukaryote cells including mitochondria biogenesis and energy homeostasis. Here we identify a patient with hypotonia, weakness, delayed milestones and neurological impairment since birth harbouring a novel homozygous mutation in the AMPK catalytic alpha-subunit 1, encoded by the PRKAA1 gene. The homozygous mutation p.S487L in isoform 1 present in the patient is in a cryptic residue for AMPK activity. In the present study, we performed the characterization of mitochondrial respiratory properties of the patient, in comparison to healthy controls, through the culture of skin fibroblasts in order to understand some of the cellular consequences of the PRKAA1 mutation. In these assays, mitochondrial respiratory complex I showed lower activity, which was followed by a decrement in the mtDNA copy number, which is a probable consequence of the lower expression of PGC-1 alpha and PRKAA1 itself as measured in our quantitative PCRs experiments. Confirming the effect of the patient mutation in respiration, transfection of patient fibroblasts with wild type PRKAA1 partially restore complex I level. The preliminary clinic evaluations of the patient suggested a metabolic defect related to the mitochondrial respiratory function, therefore treatment with CoQ10 supplementation dose started four years ago and a clear improvement in motor skills and strength has been achieved with this treatment. (AU)

• FAPESP's process: 10/51924-0 - Identification of patients with metabolic defect in coenzyme Q10
• Grantee: Claudia Cristina Ferreiro de Barros
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/07366-5 - Study of mitochondrial proteins of unknown function and their respective effects on cell viability
• Grantee: Mario Henrique de Barros
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/23549-3 - Metabolomics, lipidomics and mitochondrial biogenesis studies in neural progenitor cells derived from patients' fibroblasts with coenzyme Q10 deficiency.
• Grantee: Claudia Cristina Ferreiro de Barros
• Support Opportunities: Regular Research Grants