Mitochondrial hexokinase II promotes neuronal survival and acts downstream of glycogen synthase kinase-3.
Mitochondrial alterations are detected in most neurodegenerative disorders and may contribute to the dysfunction and demise of neuronal cells. Because glycogen synthase kinase-3 (GSK-3) is considered to be a critical factor in regulating neuronal cell survival and death, we studied the effects of modulating GSK-3 activity in cultured neurons treated with the mitochondrial inhibitor, rotenone. Interestingly, chronic inhibition of GSK-3 protects against rotenone-induced apoptosis in cultured neuronal cells. In an attempt to elucidate the molecular mechanisms underlying this neuroprotection, we demonstrated that chronic inhibition of GSK-3 reprograms the metabolism of neuronal cells, leading to an enhancement of glycolysis. This effect was accompanied by the induction and accumulation of hexokinase II (HKII) in the mitochondria. Interfering with either the mitochondrial binding of HKII or HKII expression significantly diminished the neuroprotection evoked by GSK-3 inhibition, and importantly, HKII overexpression is sufficient to protect against rotenone-induced cell death. Thus, mitochondrial HKII is a promoter of neuronal survival under the regulation of GSK-3. Furthermore, the neuroprotective effect of HKII may be relevant to neurodegenerative diseases in which glucose hypometabolism and mitochondrial dysfunction are prominent features.
Gimenez-Cassina
Alfredo
A
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas, UAM, Campus de Cantoblanco, 28049 Madrid; U-748, Area de Neurogenetica, Centro de Investigacion Biomedica en Red sobre Enfermedades Raras, CIBERER 28049, Spain.
Lim
Filip
F
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas, UAM, Campus de Cantoblanco, 28049 Madrid; U-748, Area de Neurogenetica, Centro de Investigacion Biomedica en Red sobre Enfermedades Raras, CIBERER 28049, Spain.
Cerrato
Toñi
T
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas, UAM, Campus de Cantoblanco, 28049 Madrid; U-748, Area de Neurogenetica, Centro de Investigacion Biomedica en Red sobre Enfermedades Raras, CIBERER 28049, Spain.
Palomo
Gloria M
GM
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas, UAM, Campus de Cantoblanco, 28049 Madrid; U-748, Area de Neurogenetica, Centro de Investigacion Biomedica en Red sobre Enfermedades Raras, CIBERER 28049, Spain.
Diaz-Nido
Javier
J
Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas, UAM, Campus de Cantoblanco, 28049 Madrid; U-748, Area de Neurogenetica, Centro de Investigacion Biomedica en Red sobre Enfermedades Raras, CIBERER 28049, Spain. Electronic address: javier.diaznido@uam.es.
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D005260:Female; D005455:Fluorescent Antibody Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D012402:Rotenone; D006593:Hexokinase; D038362:Glycogen Synthase Kinase 3