Bartolome, Fernando, Esteras, Noemi, Martin-Requero, Angeles, Boutoleau-Bretonniere, Claire, Vercelletto, Martine, Gabelle, Audrey, Le Ber, Isabelle, Honda, Tadashi, Dinkova-Kostova, Albena T., Hardy, John, Carro, Eva, Abramov, Andrey Y., Motor Neuron Disease Association, Wellcome Trust, University of Sheffield, University of Dundee, University College London, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Fundación Mutua Madrileña, Fundación Ramón Areces, Bartolomé Robledo, Fernando, Esteras, Noemí, Martín-Requero, Ángeles, Boutoleau-Bretonnière, Claire, Gabelle, Audrey, Ber, Isabelle Le, Honda, Tadashi, Dinkova-Kostova, Albena T., Hardy, John A., Carro, Eva, Abramov, Andrey Yurevich, Bartolomé Robledo, Fernando [0000-0001-9322-8933], Esteras, Noemí [0000-0002-7938-6131], Martín-Requero, Ángeles [0000-0002-3416-9440], Boutoleau-Bretonnière, Claire [0000-0001-9051-6315], Gabelle, Audrey [0000-0002-7648-9194], Ber, Isabelle Le [0000-0002-2508-5181], Honda, Tadashi [0000-0003-0746-9453], Dinkova-Kostova, Albena T. [0000-0003-0316-9859], Hardy, John A. [0000-0002-3122-0423], Carro, Eva [0000-0002-6504-4579], and Abramov, Andrey Yurevich [0000-0002-7646-7235]
14 p.-6 fig.-1 tab., Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain.This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH)levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency., This work was supported by a career development award from the MRC (G0700183), by an ALS Association Initiated award (ID#2109) by the Motor Neuron Disease Association, partially by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson’s Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. AMR is supported by grant CTQ2015-66313-R from MINECO, Spain.ILB has received funding from the program “Investissements d’avenir” ANR-10-IAIHU-06, FP7-Neuromics,PHRC FTLD-exomes. EC is supported by grants from the Instituto de Salud Carlos III (FIS2012/00486;BA14/00058), FEDER, Fundación Investigación Médica Mutua Madrileña (2010/0004), Fundación Ramón Areces (CIVP16A1825), and CIBERNED.