Raising NAD + Level Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein Deacetylation Article Swipe
Matthew Walker
,
Hongye Chen
,
Aprajita S. Yadav
,
Julia Ritterhoff
,
Outi Villet
,
Timothy S. McMillen
,
Yuliang Wang
,
Hayley Purcell
,
Danijel Djukovic
,
Daniel Raftery
,
Nina Isoherranen
,
Rong Tian
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1161/circulationaha.123.066039
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1161/circulationaha.123.066039
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.
Related Topics
Concepts
SIRT3
NAD+ kinase
Sirtuin
Nicotinamide adenine dinucleotide
Mitochondrion
Sirtuin 1
Biology
Biochemistry
Downregulation and upregulation
Enzyme
Gene
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1161/circulationaha.123.066039
- OA Status
- green
- Cited By
- 28
- References
- 81
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4388701802
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4388701802Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1161/circulationaha.123.066039Digital Object Identifier
- Title
-
Raising NAD + Level Stimulates Short-Chain Dehydrogenase/Reductase Proteins to Alleviate Heart Failure Independent of Mitochondrial Protein DeacetylationWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-11-15Full publication date if available
- Authors
-
Matthew Walker, Hongye Chen, Aprajita S. Yadav, Julia Ritterhoff, Outi Villet, Timothy S. McMillen, Yuliang Wang, Hayley Purcell, Danijel Djukovic, Daniel Raftery, Nina Isoherranen, Rong TianList of authors in order
- Landing page
-
https://doi.org/10.1161/circulationaha.123.066039Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://pmc.ncbi.nlm.nih.gov/articles/PMC10842390/pdf/nihms-1940715.pdfDirect OA link when available
- Concepts
-
SIRT3, NAD+ kinase, Sirtuin, Nicotinamide adenine dinucleotide, Mitochondrion, Sirtuin 1, Biology, Biochemistry, Downregulation and upregulation, Enzyme, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
28Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 18, 2024: 10Per-year citation counts (last 5 years)
- References (count)
-
81Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| publication_date | 2023-11-15 |
| publication_year | 2023 |
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