Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1.
Mitochondrial dysfunctions accompany several neurodegenerative disorders and contribute to disease pathogenesis among others in Parkinson's disease (PD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a major regulator of mitochondrial functions and biogenesis, and was suggested as a therapeutic target in PD. PGC-1α is regulated by both transcriptional and posttranslational events involving also the action of growth factors. Fibroblast growth factor-21 (FGF21) is a regulator of glucose and fatty acid metabolism in the body but little is known about its action in the brain. We show here that FGF21 increased the levels and activity of PGC-1α and elevated mitochondrial antioxidants in human dopaminergic cells in culture. The activation of PGC-1α by FGF21 occurred via the NAD(+)-dependent deacetylase Sirtuin-1 (SIRT1) subsequent to an increase in the enzyme, nicotinamide phosphoribosyltransferase (Nampt). FGF21 also enhanced mitochondrial respiratory capacity in human dopaminergic neurons as shown in real-time analyses of living cells. FGF21 is present in the brain including midbrain and is expressed by glial cells in culture. These results show that FGF21 activates PGC-1α and increases mitochondrial efficacy in human dopaminergic neurons suggesting that FGF21 could potentially play a role in dopaminergic neuron viability and in PD.
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.
Johanna
J
Mäkelä
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.
Timofey V
TV
Tselykh
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
Francesca
F
Maiorana
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland.
Ove
O
Eriksson
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.
Hai Thi
HT
Do
Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
Giuseppa
G
Mudò
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.
Laura T
LT
Korhonen
Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Corso Tukory 129, I-90134 Palermo, Italy.
Natale
N
Belluardo
Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland ; Minerva Foundation Institute for Medical Research, Biomedicum-2, FIN-00290 Helsinki, Finland.
Dan
D
Lindholm
Dopaminergic neurons; FGF21; Mitochondria; PGC-1α; Parkinson’s disease; SIRT1