Sensing and responding to energetic stress: The role of the AMPK-PGC1α-NRF1 axis in control of mitochondrial biogenesis in fish

Activation of mammalian terget of rapamycin kinase and glycogen synthase kinase‐3β accompanies abnormal accumulation of cholesterol in fibroblasts from Niemann‐Pick type C patients

“…The obtained results are shown as means ± SD (*P < 0.05, **P < 0.01 vs both control cells). 29 Due to the increasing concentration of AMP in the cell, the active site (Thr172) of the AMPKα subunit is exposed. Of the two phosphorylation target residues, that is, Ser473 and Thr308, translocation of AKT kinase to mitochondria requires phosphorylation at Ser473 by MTORC2, 27 while for localization to the mitochondrial outer membrane and intermembrane space, Thr 308 must be phosphorylated by constitutively active PDK-1.…”

Evaluating the role of NRF-1 in regulation of the goldfish COX4-1 gene in response to temperature

“…Mitochondrial proliferation in cold-acclimated fish may be a response to an energetic shortfall, representing a means to maintain energy homeostasis despite the debilitating thermodynamic effects of cold. Cold acclimation in goldfish is accompanied by increases in AMP/ATP and ADP/ATP, consistent with energetic stress (Bremer et al, 2016). The capacity for adaptive remodelling of muscle energetics in response to physiological and environmental challenges is common amongst vertebrates, yet there are differences in the genetic mechanisms that regulate mitochondria gene expression in fish versus mammals (Bremer et al, 2012).…”

“…PGC-1α, which is critical to integration of transcriptional cascades in mammalian metabolism, differs in structure in ways that suggest a distinction in function. Fish PGC-1α has mutations in its NRF-1 binding domain (LeMoine et al, 2010) that appear to leave it incapable of binding NRF-1 (Bremer et al, 2016). Likewise, PGC-1α also lacks a site that is essential for regulation by AMPK (Bremer et al, 2016), which is a critical energy transducer in eukaryotes.…”

“…Fish PGC-1α has mutations in its NRF-1 binding domain (LeMoine et al, 2010) that appear to leave it incapable of binding NRF-1 (Bremer et al, 2016). Likewise, PGC-1α also lacks a site that is essential for regulation by AMPK (Bremer et al, 2016), which is a critical energy transducer in eukaryotes. While this may cast doubt on the role of PGC-1α as a master regulator of mitochondrial biogenesis in fish, it may well be that NRF-1 plays a similar role in fish and mammals, acting through a different coactivator such as PGC-1β.…”

“…In mammals, PGC-1α is important because of its ability to interact, directly or indirectly, with many DNA-binding proteins known to affect mitochondrial genes, including NRF-1 itself (Scarpulla, 2011). Although there may be differences in the PGC-1α axis in fish and mammals, owing to structural peculiarities in several regions of PGC-1α that bind NRF-1 (LeMoine et al, 2010;Bremer et al, 2016), it is likely that the suites of DNA-binding proteins that regulate oxidative genes in mammals perform similar functions in fish. In an analysis of the effects of thermal acclimation, we identified NRF-1 as a transcription factor that increases in parallel with the observed changes in COX4-1 mRNA (Bremer et al, 2012).…”