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

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

Author Arita, Juliana Harumi Autor UNIFESP Google Scholar
Barros, Mario H. Google Scholar
Ravagnani, Felipe Gustavo Google Scholar
Ziosi, Marcello Google Scholar
Sanches, Livia Rentas Google Scholar
Picosse, Fabíola Rosa Autor UNIFESP Google Scholar
Lopes, Tania Oliveira Google Scholar
Aguiar, Patricia de Carvalho Autor UNIFESP Google Scholar
Macabelli, Carolina Habermann Google Scholar
Chiaratti, Marcos R. Google Scholar
Pedroso, Jose Luiz Autor UNIFESP Google Scholar
Quinzii, Catarina M. Google Scholar
Barsottini, Orlando Graziani Povoas Autor UNIFESP Google Scholar
Ferreiro-Barros, Claudia Cristina Autor UNIFESP Google Scholar
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.
Keywords AMPK
Neurological impairment
Oxidative phosphorylation
Mitochondrial diseases
xmlui.dri2xhtml.METS-1.0.item-coverage Amsterdam
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
Grant number FAPESP: 2010/51924-0
FAPESP: 2011/07366-5
FAPESP: 2013/07937-8
FAPESP: 2015/23549-3
Date 2018
Published in Biochimica Et Biophysica Acta-Molecular Basis Of Disease. Amsterdam, v. 1864, n. 5, p. 1896-1903, 2018.
ISSN 0925-4439 (Sherpa/Romeo, impact factor)
Publisher Elsevier Science Bv
Extent 1896-1903
Access rights Closed access
Type Article
Web of Science ID WOS:000430883100032

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