Research Paper Volume 12, Issue 3 pp 2275—2301

PAS kinase deficiency reduces aging effects in mice

Pilar Dongil 1, 3, *, , Ana Pérez-García 1, 3, *, , Verónica Hurtado-Carneiro 1, 2, , Carmen Herrero-de-Dios 3, , Elvira Álvarez 1, 2, *, , Carmen Sanz 2, 3, *, ,

  • 1 Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, Madrid, Spain
  • 2 Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
  • 3 Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
* Equal contribution

received: July 26, 2019 ; accepted: January 7, 2020 ; published: January 23, 2020 ;

https://doi.org/10.18632/aging.102745
How to Cite

Copyright © 2020 Dongil et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Several signaling pathways may be affected during aging. All are regulated by nutrient levels leading to a decline in mitochondrial function and autophagy and to an increase in oxidative stress. PAS Domain Kinase (PASK) is a nutrient and bioenergetic sensor. We have previously found that PASK plays a role in the control of hepatic metabolic balance and mitochondrial homeostasis. To investigate PASK’s role in hepatic oxidative stress during aging, we analyzed the mitochondrial function, glucose tolerance, insulin resistance, and lipid-related parameters in aged PASK-deficient mice. Hepatic Pask mRNA decreased in step with aging, being undetectable in aged wild-type (WT) mice. Aged PASK-deficient mice recorded lower levels of ROS/RNS compared to aged WT. The regulators of mitochondrial biogenesis, PGC1a, SIRT1 and NRF2, decreased in aged WT, while aged PASK-deficient mice recorded a higher expression of NRF2, GCLm and HO1 proteins and CS activity under fasted conditions. Additionally, aged PASK-deficient mice recorded an overexpression of the longevity gene FoxO3a, and maintained elevated PCNA protein, suggesting that hepatic cell repair mechanisms might be functional. PASK-deficient mice have better insulin sensitivity and no glucose intolerance, as confirmed by a normal HOMA-IR index. PASK may be a good target for reducing damage during aging.

Abbreviations

AMPK: AMP-activated protein kinase; ATP: Adenosine triphosphate; BNIP3: BCL2 and adenovirus E1B 19-kDa-interacting protein; CAT: Catalase; COX-IV: Cytochrome c oxidase subunit IV; CS: Citrate synthase; Cu/ZnSOD: Copper- and zinc-containing superoxide dismutase; ETC: Electronic transport chain; FIS1: Fission-1; FOXO3a: Forkhead box protein O3; GCLc: Glutamate-cysteine ligase catalytic subunit; GCLm: Glutamate-cysteine ligase modifier subunit; GPx: Glutathione peroxidase; GSH: Glutathione; HO1: Heme oxygenase-1; KEAP1: Kelch-like ECH-associated protein 1; MnSOD: Manganese superoxide dismutase; MFN1: Mitofusin-1; MFN2: Mitofusin-2; MTOR: Mammalian target of rapamycin; NRF2: Nuclear factor: erythroid-derived 2)-like 2; OPA1: Optic atrophy 1; PARKIN: E3 ubiquitin-protein ligase parkin; PASK: PAS domain protein kinase; PCNA: Proliferating cell nuclear antigen; PGC1a: Peroxisome proliferator-activated receptor γ coactivator 1α; PINK1: Phosphatase and tensin homolog: PTEN)-induced kinase 1; PPARg: Peroxisome proliferator-activated receptor gamma; p21: cyclin-dependent kinase inhibitor 1; p53: tumor protein; ROS: Reactive Oxygen Species; RNS: Reactive Nitrogen Species; SIRT1: sirtuin 1.