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Open AccessFeature PaperArticle

IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β–Nrf2–BNIP3 Pathway

Cell Biology Laboratory, School of Biochemistry and Cell Biology, BioSciences Institute, University College Cork, Cork T12 YT20, Ireland
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Cells 2020, 9(1), 147; https://doi.org/10.3390/cells9010147
Received: 16 November 2019 / Revised: 20 December 2019 / Accepted: 3 January 2020 / Published: 8 January 2020
The Insulin-like Growth Factor I (IGF-1) signalling pathway is essential for cell growth and facilitates tumourogenic processes. We recently reported that IGF-1 induces a transcriptional programme for mitochondrial biogenesis, while also inducing expression of the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), suggesting that IGF-1 has a key mitochondria-protective role in cancer cells. Here, we investigated this further and delineated the signaling pathway for BNIP3 induction. We established that IGF-1 induced BNIP3 expression through a known AKT serine/threonine kinase 1 (AKT)-mediated inhibitory phosphorylation on Glycogen Synthase Kinase-3β (GSK-3β), leading to activation of Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2/Nrf2) and acting through the downstream transcriptional regulators Nuclear Respiratory Factor-1 (NRF1) and Hypoxia-inducible Factor 1 subunit α (HIF-1α). Suppression of IGF-1 signaling, Nrf2 or BNIP3 caused the accumulation of elongated mitochondria and altered the mitochondrial dynamics. IGF-1R null Mouse Embryonic Fibroblasts (MEFs) were impaired in the BNIP3 expression and in the capacity to mount a cell survival response in response to serum deprivation or mitochondrial stress. IGF-1 signalling enhanced the cellular capacity to induce autophagosomal turnover in response to activation of either general autophagy or mitophagy. Overall, we conclude that IGF-1 mediated a mitochondria-protective signal that was coordinated through the cytoprotective transcription factor Nrf2. This pathway coupled mitochondrial biogenesis with BNIP3 induction, and increased the cellular capacity for autophagosome turnover, whilst enhancing survival under conditions of metabolic or mitochondrial stress. View Full-Text
Keywords: IGF-1; IGF-1R; cancer; NFE2L2/Nrf2; BNIP3; NRF1; HIF-1α; autophagy; mitophagy; cell death IGF-1; IGF-1R; cancer; NFE2L2/Nrf2; BNIP3; NRF1; HIF-1α; autophagy; mitophagy; cell death
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MDPI and ACS Style

Riis, S.; Murray, J.B.; O’Connor, R. IGF-1 Signalling Regulates Mitochondria Dynamics and Turnover through a Conserved GSK-3β–Nrf2–BNIP3 Pathway. Cells 2020, 9, 147.

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