Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1.
The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF1) blocks the reversal of the F1Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration. By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo-ATPsynthase expression ratio occurs in neurons. This increased IF1 level is essential to induce accumulation of the PTEN-induced putative kinase 1 (PINK-1) and recruitment of the mitophagic ubiquitin ligase PARK-2 to promote autophagic "control" of the mitochondrial population. In IF1 overexpressing neurons ATP depletion is reduced during hypoxia/ischemia and the mitochondrial membrane potential (ΔYm) resilient to re-oxygenation as well as resistant to electrogenic, Ca(2+) dependent depolarization. These data suggest that in mammalian neurons mitochondria adapt to respiratory stress by upregulating IF1, which exerts a protective role by coordinating pro-survival cell mitophagy and bioenergetics resilience.
Department of Biology, University of Rome "TorVergata", 00133 Rome, Italy.
Ivana
I
Matic
EBRI-European Brain Research Institute, 00143 Rome, Italy.
Stefania
S
Cocco
Department of Biology, University of Rome "TorVergata", 00133 Rome, Italy; Regina Elena-National Cancer Institute, 00144 Rome, Italy.
Caterina
C
Ferraina
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street NW1 0TU, United Kingdom.
Rebeca
R
Martin-Jimenez
EBRI-European Brain Research Institute, 00143 Rome, Italy.
Fulvio
F
Florenzano
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street NW1 0TU, United Kingdom.
James
J
Crosby
EBRI-European Brain Research Institute, 00143 Rome, Italy.
Ramona
R
Lupi
EBRI-European Brain Research Institute, 00143 Rome, Italy.
Giusy
G
Amadoro
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street NW1 0TU, United Kingdom.
Claire
C
Russell
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Italy; Department of Molecular Neuroscience, Institute of Neurology, University College London, United Kingdom.
Giuseppe
G
Pignataro
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Italy; Department of Molecular Neuroscience, Institute of Neurology, University College London, United Kingdom.
Lucio
L
Annunziato
Department of Molecular Neuroscience, Institute of Neurology, University College London, United Kingdom.
Andrey Y
AY
Abramov
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street NW1 0TU, United Kingdom; UCL Consortium for Mitochondrial Research, Royal College Street, University of London, United Kingdom; Department of Biology, University of Rome "TorVergata", 00133 Rome, Italy; Regina Elena-National Cancer Institute, 00144 Rome, Italy. Electronic address: mcampanella@rvc.ac.uk.
Michelangelo
M
Campanella
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D015854:Up-Regulation; D000097795:ATPase Inhibitory Protein
D000255:Adenosine Triphosphate; D011506:Proteins; D000097795:ATPase Inhibitory Protein
Cyclosporine A (PubChem CID: 5284373); F(1)F(o)-ATPsynthase; FCCP (PubChem: CID 3330); Ferrutinin (PubChem: CID 354654); Hypoxia/ischemia; IF(1); Magnesim green (PubChem CID: 197702); Methylthiazoletetrazolium (PubChem CID: 64965); Mitophagy; Re-oxygenation; Tetramethylrhodamine methyl ester perchlorate (PubChem CID: 11755725); ΔΨ(m)