Journal
JOURNAL OF CELL SCIENCE
Volume 122, Issue 24, Pages 4516-4525Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.049734
Keywords
ERK; ERR alpha; Growth; Mitochondria; PI3K
Categories
Funding
- FEBS
- CRUK Senior Cancer Research Fellow
- CRUK programme
- Medical Research Council [G0601943] Funding Source: researchfish
- MRC [G0601943] Funding Source: UKRI
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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 alpha. 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.
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