Xrn1 Modulates Mitochondrial NAD Levels through NAD-Capped RNA Decay
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Saccharomyces Cerevisiae (ncbitaxon:4932)
SUBMITTER: 
Megerditch Kiledjian
PROVIDER: MSV000087605 | MassIVE | Thu Jun 10 12:10:00 BST 2021
REPOSITORIES: MassIVE
Similar Datasets
Project description:Poly ADP-ribose (PAR) polymerases (PARPs) play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and PARylation. The existence of mtPARP is controversial, and the biological roles for mtPARP induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induces PARylation which is suppressed by PARP inhibitor olaparib treatment. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA) labeling. To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) . We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and NAD+ dependent mtPARP1 activity contributes to mtDNA transcription regulation.
2022-08-20 | GSE182533 | GEO
Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.
2020-12-22 | GSE144556 | GEO
Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.
2020-12-22 | GSE144557 | GEO
Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE78256 | GEO
Project description:The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation.
2017-08-18 | GSE70015 | GEO
Project description:Metabolic dysfunction is a primary feature of the premature aging Werner syndrome (WS), a heritable human disease caused by mutations in the gene encoding the DNA helicase Werner (WRN). However, the relationship between WRN mutation and its severe metabolic phenotypes is unclear. Here we report mitochondrial dysfunction and depletion of NAD+, a fundamental ubiquitous cofactor, in WS patient samples and WS animal models. NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably delays accelerated aging, including stem cell dysfunction in both C. elegans and Drosophila models of WS. Mechanistically, WRN physically binds to a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) and facilitates its NAD+ production. Our findings reveal an unprecedented anti-aging mechanism of WRN that integrates its new function of NAD+ synthesis to coordinate mitochondrial maintenance and energy expenditure, and suggest therapeutic potential.
2019-08-16 | GSE108968 | GEO
Project description:Mitochondrial complex I regenerates NAD+ and proton pumps for TCA cycle function and ATP production, respectively. Mitochondrial complex I dysfunction has been implicated in many brain pathologies including Leigh Syndrome and Parkinson’s disease. We sought to determine whether NAD+ regeneration or proton pumping is the dominant function of mitochondrial complex I in protection from brain pathology. We generated a mouse that conditionally expresses the yeast NDI1 protein, a single enzyme that can replace the NAD+ regeneration capability of the 45-subunit mammalian mitochondrial complex I without proton pumping. NDI1 expression was sufficient to dramatically prolong lifespan without significantly improving motor function in a mouse model of Leigh Syndrome. Therefore, mitochondrial complex I activity in the brain supports organismal survival through its NAD+ regeneration capacity, while optimal motor control requires the bioenergetic function of mitochondrial complex I.
2020-04-30 | GSE149616 | GEO
Project description:Mitochondrial PARP1 Regulates NAD+-dependent Poly ADP-ribosylation on Mitochondrial Nucleoids
| PRJNA756682 | ENA
Project description:Background: Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of all of the beneficial interventions implemented in patients with diabetes, there remains a need for additional therapeutic targets in diabetic kidney disease (DKD). Mitochondrial dysfunction and inflammation are increasingly recognized as important causes of the development and progression of DKD. However, the molecular connection between mitochondrial function, inflammation, and fibrosis remains to be elucidated. Methods: In the present studies we tested the hypothesis that enhancing NAD metabolism could increase mitochondrial sirtuin 3 (SIRT3) activity, improve mitochondrial function, decrease mitochondrial DNA damage, and prevent inflammation and progression of DKD. Results: We found that treatment of db-db mice with type 2 diabetes with nicotinamide riboside (NR) prevented albuminuria, increased urinary KIM1 excretion, and several parameters of DKD. These effects were associated with increased SIRT3 activity, improved mitochondrial function, and decreased inflammation at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. Conclusions: NR supplementation boosted the NAD metabolism to modulate mitochondrial function and inflammation and prevent progression of diabetic kidney disease.
2023-08-02 | PXD029745 | Pride
Project description:BACKGROUND: Strategies to increase cellular NAD+ (oxidized nicotinamide adenine dinucleotide) level have prevented cardiac dysfunction in multiple models of heart failure, but molecular mechanisms remain unclear. Little is known about the benefits of NAD+-based therapies in failing hearts after the symptoms of heart failure have appeared. Most pretreatment regimens suggested mechanisms involving activation of sirtuin, especially Sirt3 (sirtuin 3), and mitochondrial protein acetylation. METHODS: We induced cardiac dysfunction by pressure overload in SIRT3-deficient (knockout) mice and compared their response with nicotinamide riboside chloride treatment with wild-type mice. To model a therapeutic approach, we initiated the treatment in mice with established cardiac dysfunction. RESULTS: We found nicotinamide riboside chloride improved mitochondrial function and blunted heart failure progression. Similar benefits were observed in wild-type and knockout mice. Boosting NAD+ level improved the function of NAD(H) redox sensitive SDR (short-chain dehydrogenase/reductase) family proteins. Upregulation of Mrpp2 (mitochondrial ribonuclease P protein 2), a multifunctional SDR protein and a subunit of mitochondrial ribonuclease P, improves mitochondrial DNA transcripts processing and electron transport chain function. Activation of SDRs in the retinol metabolism pathway stimulates RXRα (retinoid X receptor α)/PPARα (proliferator-activated receptor α) signaling and restores mitochondrial oxidative metabolism. Downregulation of Mrpp2 and impaired mitochondrial ribonuclease P were found in human failing hearts, suggesting a shared mechanism of defective mitochondrial biogenesis in mouse and human heart failure. CONCLUSIONS: These findings identify SDR proteins as important regulators of mitochondrial function and molecular targets of NAD+-based therapy. Furthermore, the benefit is observed regardless of Sirt3-mediated mitochondrial protein deacetylation, a widely held mechanism for NAD+-based therapy for heart failure. The data also show that NAD+-based therapy can be useful in pre-existing heart failure.
2024-11-27 | GSE282759 | GEO