PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation

Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.

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“…All steps were performed on the machine with Ventana solutions. EM was performed as described in (Bai et al , 2011). …”

Section: Methodsmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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“…Interestingly, the brown adipose tissue was not involved in the development of the energy expenditure phenotype in contrast to PARP-1 -/-mice [62,87] The increased energy expenditure fuelled by enhanced mitochondrial biogenesis in skeletal muscle and liver had beneficial effects on the metabolism of PARP-2 -/-mice. PARP-2 -/-mice are protected against diet-induced obesity, and insulin resistance of the animals was retained even after high fat feeding [62].…”

Section: The Role Of Parp-2 In Metabolic Regulationmentioning

confidence: 98%

“…SIRT1 is activated by increases in NAD + levels, or indirectly by different small molecule activators such as resveratrol [84], SIRT1720 [85], AMPK activators [86] or PARP inhibitors [87]. SIRT1 activation leads to the deacetylation and activation of numerous metabolic transcription factors such as PPAR gamma coactivator (PGC)-1 [88], FOXOs [89] and p53 [90].…”

Section: Interaction With Sirt1mentioning

confidence: 99%

“…It must be noted that the ablation, or pharmacological inhibition of PARP-1 also induces SIRT1 activity. However SIRT1 activation in the absence of PARP-1 depends on enhanced NAD + availability and the ablation of PARP-1 does not alter the activity of the SIRT1 promoter [87]. The action of PARP-2 has been shown in multiple organs and tissues such as skeletal muscle, liver, smooth muscle [33,62] and an unexpected diadvantageous effect has been shown in the pancreas [62].…”

Section: Interaction With Sirt1mentioning

confidence: 99%

“…Since SIRT1 has been demonstrated to enhance or restore mitochondrial activity in various tissues [62,87,91,[109][110][111] it is logical to assume that the interference between PARP-2 and SIRT1 expression [62] could be key for the protective phenotype. Indeed, in the case of doxorubicin-induced vascular damage, enhanced SIRT1 expression and consequent stabilization of the mitochondrial membrane potential was proposed to be responsible for the protection provided by the PARP-2 -/-phenotype [33] which might be a prototypical mechanism by which PARP-2 mediates oxidative stress-related pathologies.…”

Section: Parp-2 In Oxidative Stress-related Diseasesmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

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Simultaneous measurement of NAD metabolome in aged mice tissue using liquid chromatography tandem‐mass spectrometry

Yaku

Okabe

Nakagawa

2018

Biomedical Chromatography

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Nicotinamide adenine dinucleotide (NAD) is a major co-factor that mediates multiple biological processes including redox reaction and gene expression. Recently, NAD metabolism has received considerable attention because administration of NAD precursors exhibited beneficial effects against aging-related metabolic disorders in animals. Although numerous studies have reported that NAD levels decline with aging in multiple animal tissues, the pathway and kinetics of NAD metabolism in aged organs are not completely understood. To determine the NAD metabolism upon aging, we developed targeted metabolomics based on an LC/MS/MS system. Our method is simple and applicable to crude biological samples, including culture cells and animal tissues. Unlike a conventional enzymatic cycling assay, our approach can determine NAD and NADH (reduced form of NAD) by performing a single sample preparation. Further, we validated our method using biological samples and investigated the alteration of the NAD metabolome during aging. Consistent with previous reports, the NAD levels in the liver and skeletal muscle decreased with aging. Further, we detected a significant increase in nicotinamide mononucleotide and nicotinamide riboside in the kidney upon aging. The LC/MS/MS-based NAD metabolomics that we have developed is extensively applicable to biomedical studies, and the results will present innovative ideas for the aging studies, especially for that of NAD metabolism.

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PARP-1 Inhibition Increases Mitochondrial Metabolism through SIRT1 Activation

Cited by 712 publications

References 28 publications

Mfn2 is critical for brown adipose tissue thermogenic function

Mfn2 is critical for brown adipose tissue thermogenic function

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Simultaneous measurement of NAD metabolome in aged mice tissue using liquid chromatography tandem‐mass spectrometry

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