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First published online 17 November 2009
doi: 10.1242/jcs.049734

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Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

¹ MRC Laboratory for Molecular Cell Biology and The Cancer Institute, University College London, WC1E 6BT, London, UK
² Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT, London, UK
³ CRUK Bioinformatics and Biostatistics, LRI, London, UK

^* Author for correspondence (alison.lloyd{at}ucl.ac.uk)

Accepted 22 September 2009

Cells generate new organelles when stimulated by extracellular factors to grow and divide; however, little is known about how growth and mitogenic signalling pathways regulate organelle biogenesis. Using mitochondria as a model organelle, we have investigated this problem in primary Schwann cells, for which distinct factors act solely as mitogens (neuregulin) or as promoters of cell growth (insulin-like growth factor 1; IGF1). We find that neuregulin and IGF1 act synergistically to increase mitochondrial biogenesis and mitochondrial DNA replication, resulting in increased mitochondrial density in these cells. Moreover, constitutive oncogenic Ras signalling results in a further increase in mitochondrial density. This synergistic effect is seen at the global transcriptional level, requires both the ERK and phosphoinositide 3-kinase (PI3K) signalling pathways and is mediated by the transcription factor ERR. Interestingly, the effect is independent of Akt-TOR signalling, a major regulator of cell growth in these cells. This separation of the pathways that drive mitochondrial biogenesis and cell growth provides a mechanism for the modulation of mitochondrial density according to the metabolic requirements of the cell.

Key words: ERK, ERR, Growth, Mitochondria, PI3K

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