title: Sensing and responding to energetic stress: The role of the AMPK-PGC1α-NRF1 axis in control of mitochondrial biogenesis in fish.
abstract: Remodeling the muscle metabolic machinery in mammals in response to energetic challenges depends on the energy sensor AMP-activated protein kinase (AMPK) and its ability to phosphorylate PPAR γ coactivator 1 α (PGC1α), which in turn coactivates metabolic genes through direct and indirect association with DNA-binding proteins such as the nuclear respiratory factor 1 (NRF1) (Wu et al., 1999). The integrity of this axis in fish is uncertain because PGC1α i) lacks the critical Thr177 targeted by AMPK and ii) has mutations that may preclude binding NRF1. In this study we found no evidence that AMPK regulates mitochondrial gene expression through PGC1α in zebrafish and goldfish. AICAR treatment of zebrafish blastula cells increased phosphorylation of AMPK and led to changes in transcript levels of the AMPK targets mTOR and hexokinase 2. However, we saw no increases in mRNA levels for genes associated with mitochondrial biogenesis, including PGC1α, NRF1, and COX7C, a cytochrome c oxidase subunit. Further, AMPK phosphorylated mammalian peptides of PGC1α but not the corresponding region of zebrafish or goldfish in vitro. In vivo cold acclimation of goldfish caused an increase in mitochondrial enzymes, AMP and ADP levels, however AMPK phosphorylation decreased. In fish, the NRF1-PGC1α axis may be disrupted due to insertions in fish PGC1α orthologs within the region that serves as NRF1 binding domain in mammals. Immunocopurification showed that recombinant NRF1 protein binds mammalian but not fish PGC1α. Collectively, our studies suggest that fish have a disruption in the AMPK-PGC1α-NRF1 pathway due to structural differences between fish and mammalian PGC1α.
authors.affiliation: Department of Biology, Queen's University, Biosciences Complex, 116 Barrie Street, Kingston, ON K7L 3N6, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Bremer
authors.affiliation: Department of Biology, Queen's University, Biosciences Complex, 116 Barrie Street, Kingston, ON K7L 3N6, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Kocha
authors.affiliation: Department of Biology, Queen's University, Biosciences Complex, 116 Barrie Street, Kingston, ON K7L 3N6, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Snider
authors.affiliation: Department of Biology, Queen's University, Biosciences Complex, 116 Barrie Street, Kingston, ON K7L 3N6, Canada. Electronic address: Chris.Moyes@queensu.ca.
authors.forename: C D
authors.initials: CD
authors.lastname: Moyes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation; D005399:Fishes / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013312:Stress, Physiological
chemical_list: D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; Evolution of energy metabolism; Muscle mitochondria; Nuclear respiratory factor 1; PPAR γ coactivator 1 α