Abstract
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD+ levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain. Under these conditions of compromised respiration, mitochondrial membrane potential and ATP contents are reduced, and cytosolic reactive oxygen species (ROS) production is increased. ROS activates poly (ADP-ribose) polymerase (PARP) activity in Fbxo7-deficient cells. PARP inhibitor restores cellular NAD+ content and redox index and ATP pool, suggesting that PARP overactivation is cause of decreased complex I-driven respiration. These findings bring new insight into the mechanism of Fbxo7 deficiency, emphasising the importance of mitochondrial dysfunction in PD.
MeSH terms
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Adenosine Triphosphate / metabolism
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Cells, Cultured
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Electron Transport Complex I / antagonists & inhibitors
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Electron Transport Complex I / metabolism
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F-Box Proteins / antagonists & inhibitors
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Humans
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Iodoacetic Acid / pharmacology
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Isoquinolines / pharmacology
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitophagy / drug effects
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NAD / chemistry
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NAD / metabolism
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Oxygen Consumption
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Parkinson Disease / genetics
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Parkinson Disease / metabolism
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Parkinson Disease / pathology*
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Piperidines / pharmacology
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Poly(ADP-ribose) Polymerases / chemistry
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Poly(ADP-ribose) Polymerases / metabolism*
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Polymorphism, Single Nucleotide
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RNA Interference
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism
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Sodium Cyanide / pharmacology
Substances
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F-Box Proteins
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FBXO7 protein, human
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Isoquinolines
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors
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RNA, Small Interfering
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Reactive Oxygen Species
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NAD
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3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone
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Adenosine Triphosphate
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Poly(ADP-ribose) Polymerases
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Electron Transport Complex I
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Sodium Cyanide
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Iodoacetic Acid