Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis.
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 ERRalpha. 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.
Echave
Pedro
P
MRC Laboratory for Molecular Cell Biology, The Cancer Institute, University College London, London, UK.
Machado-da-Silva
Gisela
G
Arkell
Rebecca S
RS
Duchen
Michael R
MR
Jacobson
Jake
J
Mitter
Richard
R
Lloyd
Alison C
AC
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008934:Mitogens / Q000378:metabolism*; D020880:Neuregulins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism*; D015398:Signal Transduction
D008934:Mitogens; D020880:Neuregulins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases