Mitochondrial Localization of PARP-1 Requires Interaction with Mitofilin and Is Involved in the Maintenance of Mitochondrial DNA Integrity

Rossi, Marianna Nicoletta; Carbone, Mariarosaria; Mostocotto, Cassandra; Mancone, Carmine; Tripodi, Marco; Maione, Rossella; Amati, Paolo

doi:10.1074/jbc.m109.025882

Cited by 149 publications

(144 citation statements)

References 46 publications

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“…3,4 Protein kinase C epsilon-mediated increases in mitochondrial NAD þ availability may help to maintain pools of NAD þ during activity of mitochondrial-localized PARPs (Figure 7), thereby maintaining mitochondrial DNA integrity and preventing cell death. 18,39 The protective role of Nampt against neurodegenerative damage has recently become the focus of intense investigation. 40 In this study, we have expanded the focus to understand how mitochondrial pools of Nampt, NAD, and the NAD þ /NADH ratio are regulated by a PKCe-AMPK pathway during IPC and resveratrol treatment.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Morris-Blanco

Cohan

Neumann

et al. 2014

J Cereb Blood Flow Metab

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Preserving mitochondrial pools of nicotinamide adenine dinucleotide (NAD) or nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in NAD production, maintains mitochondrial function and confers neuroprotection after ischemic stress. However, the mechanisms involved in regulating mitochondrial-localized Nampt or NAD have not been defined. In this study, we investigated the roles of protein kinase C epsilon (PKCe) and AMP-activated protein kinase (AMPK) in regulating mitochondrial pools of Nampt and NAD after resveratrol or ischemic preconditioning (IPC) in the cortex and in primary neuronal-glial cortical cultures. Using the specific PKCe agonist ceRACK, we found that PKCe induced robust activation of AMPK in vitro and in vivo and that AMPK was required for PKCe-mediated ischemic neuroprotection. In purified mitochondrial fractions, PKCe enhanced Nampt levels in an AMPK-dependent manner and was required for increased mitochondrial Nampt after IPC or resveratrol treatment. Analysis of intrinsic NAD autofluorescence using two-photon microscopy revealed that PKCe modulated NAD in the mitochondrial fraction. Further assessments of mitochondrial NAD concentrations showed that PKCe has a key role in regulating the mitochondrial NAD þ / nicotinamide adenine dinucleotide reduced (NADH) ratio after IPC and resveratrol treatment in an AMPK-and Nampt-dependent manner. These findings indicate that PKCe is critical to increase or maintain mitochondrial Nampt and NAD after pathways of ischemic neuroprotection in the brain.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Morris-Blanco

Cohan

Neumann

et al. 2014

J Cereb Blood Flow Metab

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“…A shortened form of APE1 is expressed in the mitochondria, as is APE2 (Table 4). DNA ligase IIIa is expressed in both the nucleus and the mitochondria, but not XRCC1, whereas PARP1 is expressed in the mitochondria only in the (76). Although Polb is not expressed in mitochondria (37), the mitochondrial DNA polymerase g has the requisite DNA polymerase activity, as well as a 5 0 -dRP lyase function, implicating DNA polymerase g in mitochondrial BER (56).…”

Section: Mitochondrial Base Excision Repairmentioning

confidence: 99%

Base Excision Repair and Lesion-Dependent Subpathways for Repair of Oxidative DNA Damage

Svilar

Goellner

Almeida

et al. 2011

Antioxidants & Redox Signaling

228

225

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Nuclear and mitochondrial genomes are under continuous assault by a combination of environmentally and endogenously derived reactive oxygen species, inducing the formation and accumulation of mutagenic, toxic, and=or genome-destabilizing DNA lesions. Failure to resolve these lesions through one or more DNA-repair processes is associated with genome instability, mitochondrial dysfunction, neurodegeneration, inflammation, aging, and cancer, emphasizing the importance of characterizing the pathways and proteins involved in the repair of oxidative DNA damage. This review focuses on the repair of oxidative damage-induced lesions in nuclear and mitochondrial DNA mediated by the base excision repair (BER) pathway in mammalian cells. We discuss the multiple BER subpathways that are initiated by one of 11 different DNA glycosylases of three subtypes: (a) bifunctional with an associated b-lyase activity; (b) monofunctional; and (c) bifunctional with an associated b,dlyase activity. These three subtypes of DNA glycosylases all initiate BER but yield different chemical intermediates and hence different BER complexes to complete repair. Additionally, we briefly summarize alternate repair events mediated by BER proteins and the role of BER in the repair of mitochondrial DNA damage induced by ROS. Finally, we discuss the relation of BER and oxidative DNA damage in the onset of human disease.

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“…This might occur either because of a possible existence of a mitochondrial PARP-1 or because of mitochondrial NAD efflux driven by reduced cytoplasmic content. Whereas the presence of PARP-1 within mitochondria is a highly controversial issue (14,(33)(34)(35), NAD fluxes across the mitochondrial membranes have been reported (36), as well as bidirectional mitochondrial NAD transporters in plants (37) and yeasts (38). A recent contribution, however, is at odds with the hypothesis that mitochondrial NAD content changes during PARP-1 hyperactivity (20).…”

Section: Discussionmentioning

confidence: 99%

Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

Buonvicino

Formentini

Cipriani

et al. 2013

Journal of Biological Chemistry

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Background: Excessive activation of enzyme poly(ADP-ribose) polymerase-1 (PARP-1) causes ATP depletion and kills cells. Results: We found that in the absence of glucose PARP-1 triggers an adenylate kinase-dependent increase of ATP. Conclusion: PARP-1 hyperactivation is not invariantly related to ATP loss. Significance: This study adds to the complexity of PARP-1 hyperactivity and energy derangement.Massive poly(ADP-ribose) formation by poly(ADP-ribose) polymerase-1 (PARP-1) triggers NAD depletion and cell death. These events have been invariantly related to cellular energy failure due to ATP shortage. The latter occurs because of both ATP consumption for NAD resynthesis and impairment of mitochondrial ATP formation caused by an increase of the AMP/ADP ratio. ATP depletion is therefore thought to be an inevitable consequence of NAD loss and a hallmark of PARP-1 activation. Here, we challenge this scenario by showing that PARP-1 hyperactivation in cells cultured in the absence of glucose (Glu ؊ cells) is followed by NAD depletion and an unexpected PARP-1 activity-dependent ATP increase. We found increased ADP content in resting Glu ؊ cells, a condition that counteracts the increase of the AMP/ADP ratio during hyperpoly(ADP-ribosyl)ation and preserves mitochondrial coupling. We also show that the increase of ATP in Glu ؊ cells is due to adenylate kinase activity, transforming AMP into ADP which, in turn, is converted into ATP by coupled mitochondria. Interestingly, PARP-1-dependent mitochondrial release of apoptosisinducing factor (AIF) and cytochrome complex (Cyt c) is reduced in Glu ؊ cells, even though cell death eventually occurs.Overall, the present study identifies basal ADP content and adenylate kinase as key determinants of bioenergetics during PARP-1 hyperactivation and unequivocally demonstrates that ATP loss is not metabolically related to NAD depletion.Poly(ADP-ribosyl)ation is a post-translational modification of proteins operated by poly(ADP-ribose) polymerases (PARPs) 2 (1). PARP-1, the oldest and best characterized member of the PARP family, is a nuclear enzyme converting NAD into polymers of poly(ADP-ribose) (PAR) that regulate chromatin-interacting proteins through steric hindrance and electrostatic repulsion (2). By so doing, the enzyme plays a key role in various nuclear process involved in maintenance of nuclear homeostasis such as DNA repair and epigenetic regulation of gene expression (3-5). Somehow paradoxically, besides this pleiotypic physiological role, PARP-1 is a powerful trigger of cell death (6, 7). This occurs when the enzymes undergo hyperactivation because of extensive DNA damage. PARP-1-dependent cell death was originally described as a necrotic process (8, 9), but an involvement of PARP-1 in apoptosis (10) and autophagy (11) has also been reported. In keeping with the central role of the enzyme in cell demise, chemical inhibitors of PARP-1 exert widespread cytoprotection in disparate in vitro and in vivo disease models (12). It has been proposed that intracellular NAD depletion a...

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Mitochondrial Localization of PARP-1 Requires Interaction with Mitofilin and Is Involved in the Maintenance of Mitochondrial DNA Integrity

Cited by 149 publications

References 46 publications

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Base Excision Repair and Lesion-Dependent Subpathways for Repair of Oxidative DNA Damage

Glucose Deprivation Converts Poly(ADP-ribose) Polymerase-1 Hyperactivation into a Transient Energy-producing Process

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