Deficiency of Parkinson\u2019s disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation

Marta Delgado-Camprubi,Helene Plun-Favreau,Andrey Y Abramov,Noemi Esteras,Marc Pm Soutar

doi:10.1038/cdd.2016.104

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.

Highlights

Mitochondrial susceptibility to age-related oxidative stress makes mitochondrial impairment a common feature of neurodegeneration.[1]
We report that Fbxo[7] deficiency is associated with cellular NAD+ depletion, limiting NADH substrate for complex I in the mitochondrial electron transport chain (ETC)
We show that poly (ADP-ribose) polymerase (PARP) pharmacologic inhibition increases cellular NAD+ levels, and restores NADH redox index and complex I NADH dehydrogenase activity that results in recovery of the ATP pool in F-box only protein 7 (Fbxo7)-deficient cells

Summary

Introduction

Mitochondrial susceptibility to age-related oxidative stress makes mitochondrial impairment a common feature of neurodegeneration.[1]. In addition to SCF-dependent activities, several FBPs participate in cellular functions, including cell cycle regulation and mitochondrial dynamics.[15] We have recently shown that, together with the PD-associated proteins, PTEN-induced putative kinase 1 (PARK6) and Parkin (PARK2), Fbxo[7] regulates the selective autophagic clearance of depolarised mitochondria (mitophagy). The PARP family includes 18 members, among which PARP-1 (hereafter referred as PARP) is responsible for the 80% of the NAD+-dependent synthesis of PAR polymers.[17] PARP prolonged activation can, cause a reduction of cellular NAD+, which in turn can lead to ATP reduction and bioenergetic collapse.[18] PARP-activated NAD+ depletion has been associated before with the pathogenesis of neurodegenerative disorders, in particular with Alzheimer’s disease[19,20,21] and glutamate excitotoxicity.[22,23]

Methods

Results

Conclusion