Mitochondrial biogenesis is required for axonal growth.
During early development, neurons undergo complex morphological rearrangements to assemble into neuronal circuits and propagate signals. Rapid growth requires a large quantity of building materials, efficient intracellular transport and also a considerable amount of energy. To produce this energy, the neuron should first generate new mitochondria because the pre-existing mitochondria are unlikely to provide a sufficient acceleration in ATP production. Here, we demonstrate that mitochondrial biogenesis and ATP production are required for axonal growth and neuronal development in cultured rat cortical neurons. We also demonstrate that growth signals activating the CaMKKβ, LKB1-STRAD or TAK1 pathways also co-activate the AMPK-PGC-1α-NRF1 axis leading to the generation of new mitochondria to ensure energy for upcoming growth. In conclusion, our results suggest that neurons are capable of signalling for upcoming energy requirements. Earlier activation of mitochondrial biogenesis through these pathways will accelerate the generation of new mitochondria, thereby ensuring energy-producing capability for when other factors for axonal growth are synthesized.
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Annika
A
Vaarmann
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Merle
M
Mandel
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Akbar
A
Zeb
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Przemyslaw
P
Wareski
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Joanna
J
Liiv
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Malle
M
Kuum
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Eva
E
Antsov
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Mailis
M
Liiv
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Michal
M
Cagalinec
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia.
Vinay
V
Choubey
Department of Pharmacology, Centre of Excellence for Translational Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 51014, Estonia allen.kaasik@ut.ee.
Allen
0000-0002-4850-3198
A
Kaasik
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004734:Energy Metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D055495:Neurogenesis; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D020930:MAP Kinase Kinase Kinases; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7
Mitochondrial biogenesis; Neuronal growth; PGC-1α; PPARGC1A