Role of PARP-1 in mitochondrial homeostasis

Kadam, Ashlesha; Jubin, Tina; Roychowdhury, Rittwika; Begum, Rasheedunnisa

doi:10.1016/j.bbagen.2020.129669

Cited by 38 publications

(24 citation statements)

References 132 publications

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“…Poly (ADP-ribose) polymerase-1 (PARP-1), as the most abundant and ubiquitous member of the family, accounts for most of the PARP activity (Ryu et al, 2015). PARP-1 plays a crucial role in the physiological cellular functions such as DNA repair, transcription, bioenergetics, mtDNA maintenance, cell death and mitophagy (Kadam et al, 2020), using NAD + as a substrate to transfer ADP-ribose units from NAD + to form ADP-ribose polymers (PAR) (Hassa and Hottiger, 2008). Several studies have suggested that PARP-1 is closely associated with the development of cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

Chen

Cheng

et al. 2021

Front. Pharmacol.

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Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.

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Section: Introductionmentioning

confidence: 99%

Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

Chen

Cheng

et al. 2021

Front. Pharmacol.

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“…PARP1 also plays crucial roles in controlling inflammatory processes via transcriptional regulation of inflammatory mediators 22 . Moreover, PARP1 has been demonstrated to be involved in mitochondrial homeostasis and mtDNA maintenance due to its location in the nucleus 23 . High mobility group box 1 protein (HMGB1) is a protein extensively expressed in eukaryotic cells.…”

Section: Introductionmentioning

confidence: 99%

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

Qiu

Qin

et al. 2021

J Cellular Molecular Medi

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Introduction Septic cardiomyopathy is a common complication of sepsis with high morbidity and mortality, but lacks specific therapy. This study aimed to reveal the role of circTLK1 and its potential mechanisms in septic cardiomyopathy. Materials and Methods The in vitro and in vivo models of septic cardiomyopathy were established. Cell viability and apoptosis were detected by CCK8, TUNEL and flow cytometry, respectively. LDH, CK, SOD, MDA, ATP, 8‐OHdG, NAD+/NADH ratio, ROS level, mitochondrial membrane potential and cytochrome C distribution were evaluated using commercial kits. qRT‐PCR and western blotting were performed to detect RNA and protein levels. Mitochondrial DNA (mtDNA) copy number and transcription were assessed by quantitative PCR. Dual‐luciferase assay, RNA immunoprecipitation and co‐immunoprecipitation were performed to verify the interaction between circTLK1/PARP1 and miR‐17‐5p. Results CircTLK1, PARP1 and HMGB1 were up‐regulated in the in vitro and in vivo models of septic cardiomyopathy. CircTLK1 inhibition restrained LPS‐induced up‐regulation of PARP1 and HMGB1. Moreover, circTLK1 knockdown repressed sepsis‐induced mtDNA oxidative damage, mitochondrial dysfunction and consequent cardiomyocyte apoptosis by inhibiting PARP1/HMGB1 axis in vitro and in vivo. In addition, circTLK1 enhanced PARP1 expression via sponging miR‐17‐5p. Inhibition of miR‐17‐5p abolished the protective effects of circTLK1 silencing on oxidative mtDNA damage and cardiomyocyte apoptosis. Conclusion CircTLK1 sponged miR‐17‐5p to aggravate mtDNA oxidative damage, mitochondrial dysfunction and cardiomyocyte apoptosis via activating PARP1/HMGB1 axis during sepsis, indicating that circTLK1 may be a putative therapeutic target for septic cardiomyopathy.

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“…Next, we asked whether the newly identified NEURL4 enzymatic activity was required for maintaining mtDNA integrity. Poly-ADP ribosylation is well established as a key regulatory process for the repair of damaged nuclear DNA (nDNA) (Azarm and Smith, 2020) and previous studies indicate it is likely to play a similar role for mtDNA, even though the identity of the responsible enzyme is unclear (Brunyanszki et al, 2016;Kadam et al, 2020;Szczesny et al, 2014). To assess NEURL4 role in this process, we first confirmed that it is found associated with mtDNA by Chromatin Immunoprecipitation (ChIP) (Fig.…”

Section: Resultsmentioning

confidence: 68%

ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)

Cardamone

Gao

Kwan

et al. 2020

Preprint

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ADP-ribosylation is a reversible post-translational modification where an ADP-ribose moiety is covalently attached to amino acid side-chains of target proteins either as mono-ADP-ribose (MARylation or MAR) or poly-ADP-ribose chains (PARylation or PAR) by a class of enzymes called ADP-ribosyltransferases (ARTs). Although ADP-ribosylation is best known for its nuclear roles, ADP-ribosylation of extra nuclear proteins is increasingly recognized as a key regulatory strategy across cellular compartments. ADP-ribosylation of mitochondrial proteins, in particular, has been widely reported, even though the extent to which ADP-ribosylation of specific proteins regulates mitochondrial functions is unclear and the exact nature of mitochondrial ART enzymes is debated.Here, we have identified Neuralized-like protein 4 (NEURL4) as a mitochondrial ART enzyme and profiled the NEURL4-dependent ADP-ribosylome in mitochondrial extracts from Hela cells by LC-MS/MS, using isobaric tandem mass tag (TMT) labeling for relative quantification. Comparison of WT and NEURL4-KO cells generated by CRISPR/Cas9 genome editing revealed that most ART activity associated with mitochondria is lost in absence of NEURL4. Putative NEURL4 targets include numerous mitochondrial proteins previously shown to be ADP-ribosylated. In particular, we show that NEURL4 enzymatic activity is required for the regulation of mtDNA integrity via poly-ADP-ribosylation of mitochondrial specific Ligase III (mtLIG3), the rate-limiting enzyme for mitochondrial DNA (mtDNA) Base Excision Repair (BER).Collectively, our studies reveal that NEURL4 acts as the main mitochondrial ART enzyme under physiological conditions and provide novel insights in the regulation of mitochondria homeostasis through ADP-ribosylation.

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Role of PARP-1 in mitochondrial homeostasis

Cited by 38 publications

References 132 publications

Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)

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