Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

Hopp, Ann-Katrin; Teloni, Federico; Bisceglie, Lavinia; Gondrand, Corentin; Raith, Fabio; Nowak, Kathrin; Muskalla, Lukas; Howald, Anna; Pedrioli, Patrick G. A.; Johnsson, Kai; Altmeyer, Matthias; Pedrioli, Deena M. Leslie; Hottiger, Michael O.

doi:10.1016/j.molcel.2020.12.034

Cited by 44 publications

(45 citation statements)

References 72 publications

(67 reference statements)

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“…That way, NAD + derived from compartments with high basal concentrations can be used to support NAD + -dependent processes in other compartments with lower basal concentrations and lower synthesis rate. In fact, our group recently observed that following stimulation with H 2 O 2 , mitochondrial NAD + is relocated to the nucleus in order to sustain the extensive PARylation that is induced following activation of ARTD1 [155]. The same phenomenon was not solely specific to H 2 O 2 , but also happened in response to other treatments that result in extensive activation of ARTD1.…”

Section: Regulation Of Intracellular Marylation By Intracellular Nad mentioning

confidence: 93%

“…Despite these difficulties, the recent synthesis of peptides with ADP-ribose-like modifications presented the first milestone for the development of pan-ADP-ribose-and MARylation-specific antibodies [172,173]. Those and similar peptides and proteins carrying different ADP-ribose-like units indeed enabled the successful generation of several polyclonal ADP-ribose-recognizing antibodies [127,155]. A comparison between some of these antibodies and the macrodomain Af1521 commonly used for MS analysis, however, revealed that for those analysis, the macrodomain still outperforms the antibodies [174].…”

Section: Antibodies Against Mar And/or Parmentioning

confidence: 99%

“…Furthermore, permeabilization of cells and subsequent incubation with 3 -azido_NAD + allowed detecting mitochondrial-localized PAR chains by confocal microscopy [171]. However, a recent analysis using ARTD1 knockout cells revealed that the observed mitochondrial ADP-ribosylation is most likely not dependent on ARTD1 [155]. To date, besides ARTD1, SIRT4, ARH3, PARG and MacroD1 are also proposed to be involved in the regulation of ADP-ribosylation in mitochondria by catalyzing either its synthesis or removal [28,29,[187][188][189][190][191][192][193].…”

Section: Adp-ribosylation In Mitochondriamentioning

confidence: 99%

“…While the enzymatic regulation of mitochondrial ADP-ribosylation remains to be fully understood, exploiting the new generation of ADP-ribosylation-specific antibodies, we recently characterized for the first time mitochondrial ADP-ribosylation in different cellular systems by IF and WB and described its dynamics following metabolic challenges, such as respiratory chain inhibition [155]. We further described an NAD + -mediated crosstalk between mitochondrial and nuclear ADP-ribosylation and highlighted the importance of mitochondrial NAD + levels for nuclear ARTD1-mediated processes.…”

Section: Adp-ribosylation In Mitochondriamentioning

confidence: 99%

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Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Hopp

Hottiger

2021

Cells

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Adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD+)-dependent post-translational modification that is found on proteins as well as on nucleic acids. While ARTD1/PARP1-mediated poly-ADP-ribosylation has extensively been studied in the past 60 years, comparably little is known about the physiological function of mono-ADP-ribosylation and the enzymes involved in its turnover. Promising technological advances have enabled the development of innovative tools to detect NAD+ and NAD+/NADH (H for hydrogen) ratios as well as ADP-ribosylation. These tools have significantly enhanced our current understanding of how intracellular NAD dynamics contribute to the regulation of ADP-ribosylation as well as to how mono-ADP-ribosylation integrates into various cellular processes. Here, we discuss the recent technological advances, as well as associated new biological findings and concepts.

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Section: Regulation Of Intracellular Marylation By Intracellular Nad mentioning

confidence: 93%

Section: Antibodies Against Mar And/or Parmentioning

confidence: 99%

Section: Adp-ribosylation In Mitochondriamentioning

confidence: 99%

Section: Adp-ribosylation In Mitochondriamentioning

confidence: 99%

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Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Hopp

Hottiger

2021

Cells

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“…During ischemia, anaerobic glycolysis of glucose produces excessive lactic acid in the ischemic cells and ultimately causes acidification in the heart ( 61 ). When oxidative phosphorylation is not supported by sufficient oxygen, ATP production is largely reduced, leading to the dysfunction of Na + -K + -ATPase and the elevation of intracellular calcium, sodium, and hydrogen concentration ( 62 , 63 ). Subsequently, cells swell while the activities of cytoplasmic enzymes are impaired.…”

Section: Sumoylation In the Pathophysiological Process Of Myocardial Infarctionmentioning

confidence: 99%

SUMOylation as a Therapeutic Target for Myocardial Infarction

Zhao

Zhang

2021

Front. Cardiovasc. Med.

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Myocardial infarction is a prevalent and life-threatening cardiovascular disease. The main goal of existing interventional therapies is to restore coronary reperfusion while few are designed to ameliorate the pathology of heart diseases via targeting the post-translational modifications of those critical proteins. Small ubiquitin-like modifier (SUMO) proteins are recently discovered to form a new type of protein post-translational modifications (PTM), known as SUMOylation. SUMOylation and deSUMOylation are dynamically balanced in the maintenance of various biological processes including cell division, DNA repair, epigenetic transcriptional regulation, and cellular metabolism. Importantly, SUMOylation plays a critical role in the regulation of cardiac functions and the pathology of cardiovascular diseases, especially in heart failure and myocardial infarction. This review summarizes the current understanding on the effects of SUMOylation and SUMOylated proteins in the pathophysiology of myocardial infarction and identifies the potential treatments against myocardial injury via targeting SUMO. Ultimately, this review recommends SUMOylation as a key therapeutic target for treating cardiovascular diseases.

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Altered cytoplasmic and nuclear ADP‐ribosylation levels analyzed with an improved ADP‐ribose binder are a prognostic factor in renal cell carcinoma

Schraml

Aimi

Zoche

et al. 2023

The Journal of Pathology CR

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ADP‐ribosylation (ADPR) of proteins is catalyzed by ADP‐ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP‐ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive in vitro to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (n = 257 and n = 241) stained with an engineered ADP‐ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high‐ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (p < 0.01 each). cyADPR proved to be an independent prognostic factor (p = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (p < 0.01) and worse patient outcome (p < 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (p < 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased ARID1A mutations in ccRCCcyADPR+++/PARP1+ compared with ccRCCcyADPR−/PARP1− (31% versus 4%; p < 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations.

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Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

Cited by 44 publications

References 72 publications

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

SUMOylation as a Therapeutic Target for Myocardial Infarction

Altered cytoplasmic and nuclear ADP‐ribosylation levels analyzed with an improved ADP‐ribose binder are a prognostic factor in renal cell carcinoma

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