Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models.

AMPK Cerebral energy metabolism PFK PGM2L1 Protein kinase N1 Stroke

Journal

Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267

Informations de publication

Date de publication:
25 Sep 2024
Historique:
received: 26 07 2024
revised: 06 09 2024
accepted: 21 09 2024
medline: 28 9 2024
pubmed: 28 9 2024
entrez: 27 9 2024
Statut: aheadofprint

Résumé

We recently identified protein kinase N1 (PKN1) as a master regulator of brain development. However, its function in the adult brain has not been clearly established. In this study, we assessed the cerebral energetic phenotype of wildtype (WT) and global Pkn1 knockout (Pkn1 Cerebral energy metabolism was analyzed by Pkn1 deficiency resulted in a remarkable upregulation of cerebral energy metabolism, in vivo and in vitro. This was due to two separate mechanisms involving an enhanced glycolytic flux and higher pyruvate-induced mitochondrial OCR. Mechanistically we show that Pkn1 This is the first study to comprehensively demonstrate an essential and unique role of PKN1 in cerebral energy metabolism, regulating both glycolysis and mitochondrial pyruvate-induced respiration. We further uncovered a highly protective phenotype of Pkn1 deficiency in both, in vitro and in vivo stroke models, validating inhibition of PKN1 as a promising new therapeutic target for the development of novel stroke therapies.

Sections du résumé

BACKGROUND AND AIM OBJECTIVE
We recently identified protein kinase N1 (PKN1) as a master regulator of brain development. However, its function in the adult brain has not been clearly established. In this study, we assessed the cerebral energetic phenotype of wildtype (WT) and global Pkn1 knockout (Pkn1
METHODS METHODS
Cerebral energy metabolism was analyzed by
RESULTS RESULTS
Pkn1 deficiency resulted in a remarkable upregulation of cerebral energy metabolism, in vivo and in vitro. This was due to two separate mechanisms involving an enhanced glycolytic flux and higher pyruvate-induced mitochondrial OCR. Mechanistically we show that Pkn1
CONCLUSION CONCLUSIONS
This is the first study to comprehensively demonstrate an essential and unique role of PKN1 in cerebral energy metabolism, regulating both glycolysis and mitochondrial pyruvate-induced respiration. We further uncovered a highly protective phenotype of Pkn1 deficiency in both, in vitro and in vivo stroke models, validating inhibition of PKN1 as a promising new therapeutic target for the development of novel stroke therapies.

Identifiants

DOI: 10.1016/j.metabol.2024.156039 PMID: 39332493
pubmed: 39332493
pii: S0026-0495(24)00267-1
doi: 10.1016/j.metabol.2024.156039
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

156039

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare no conflict of interest.

Auteurs

Stephanie Zur Nedden (SZ)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: Stephanie.zur-Nedden@i-med.ac.at.

Motahareh S Safari (MS)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Dido Weber (D)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Louisa Kuenkel (L)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Carolin Garmsiri (C)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Luisa Lang (L)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Cyrille Orset (C)

Normandie University, UNICAEN, ESR3P, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @ Caen-Normandie (BB@C), GIP Cyceron, Caen, France.

Tom Freret (T)

Normandie University, UNICAEN, ESR3P, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @ Caen-Normandie (BB@C), GIP Cyceron, Caen, France.

Benoît Haelewyn (B)

Normandie University, UNICAEN, ESR3P, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @ Caen-Normandie (BB@C), GIP Cyceron, Caen, France.

Madlen Hotze (M)

University of Innsbruck, Department of Biochemistry, Institute of Bioanalytic & Intermediary Metabolism, 6020 Innsbruck, Austria.

Marcel Kwiatkowski (M)

University of Innsbruck, Department of Biochemistry, Institute of Bioanalytic & Intermediary Metabolism, 6020 Innsbruck, Austria.

Bettina Sarg (B)

Medical University of Innsbruck, CCB-Biocenter, Institute of Medical Biochemistry, Protein Core Facility, 6020 Innsbruck, Austria.

Klaus Faserl (K)

Medical University of Innsbruck, CCB-Biocenter, Institute of Medical Biochemistry, Protein Core Facility, 6020 Innsbruck, Austria.

Dragana Savic (D)

Medical University of Innsbruck, Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, 6020 Innsbruck, Austria; Tyrolean Cancer Research Institute, Innsbruck A-6020, Austria.

Ira-Ida Skvortsova (II)

Medical University of Innsbruck, Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Department of Therapeutic Radiology and Oncology, 6020 Innsbruck, Austria; Tyrolean Cancer Research Institute, Innsbruck A-6020, Austria.

Anne Krogsdam (A)

Medical University of Innsbruck, CCB-Biocenter, Institute of Bioinformatics, 6020 Innsbruck, Austria.

Sandro Carollo (S)

Medical University of Innsbruck, CCB-Biocenter, Institute of Bioinformatics, 6020 Innsbruck, Austria.

Zlatko Trajanoski (Z)

Medical University of Innsbruck, CCB-Biocenter, Institute of Bioinformatics, 6020 Innsbruck, Austria.

Herbert Oberacher (H)

Medical University of Innsbruck, Institute of Legal Medicine and Core Facility Metabolomics, 6020 Innsbruck, Austria.

Dominik Zlotek (D)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Florian Ostermaier (F)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Angus Cameron (A)

Kinase Biology Laboratory, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Gottfried Baier (G)

Medical University of Innsbruck, Institute for Cell Genetics, 6020 Innsbruck, Austria.

Gabriele Baier-Bitterlich (G)

Medical University of Innsbruck, CCB-Biocenter, Institute of Neurobiochemistry, Innrain 80-82, A-6020 Innsbruck, Austria.

Classifications MeSH