Evidence map›Paper›PMID 27489254›Full record

ArticleCirculation2016

Normalization of NAD+ Redox Balance as a Therapy for Heart Failure.

Chi Fung Lee, Juan D Chavez, Lorena Garcia-Menendez, Yongseon Choi, Nathan D Roe, Ying Ann Chiao, John S Edgar, Young Ah Goo, David R Goodlett, James E Bruce and 1 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 223 papers.

0numbers the graph read from it
0cells of the map it votes in
223citing papers in PubMed
13.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

223 citing papers in PubMed, 326 citations in OpenAlex.

  1. Trial
  2. Review
  3. Review
  4. Article
  5. Article
  6. Article
  7. Article
  8. NADCommunications biology · 2026
    Article
  9. Article
  10. Review
  11. Article
  12. Review
  13. Review
  14. Article
  15. Review
  16. Mitochondrial Adaptation to Mechanical Stress in Cardiac Ageing and Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Review
  17. Article
  18. Review
  19. Article
  20. Mechano-energetic uncoupling in heart failure.Nature reviews. Cardiology · 2025
    Review

163 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 1 institution in 1 country.

Chi Fung LeeFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Juan D ChavezFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Lorena Garcia-MenendezFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Yongseon ChoiFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Nathan D RoeFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Ying Ann ChiaoFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
John S EdgarFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Young Ah GooFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
David R GoodlettFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
James E BruceFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.
Rong TianFrom Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA. rongtian@u.washington.edu.
United States Nuclear Regulatory Commission · US

Funding

SPECIFICITY OF OXYGEN DNA DAMAGE AND MUTAGENESISP01AG001751 · NIA · UNIVERSITY OF WASHINGTON · PI RABINOVITCH, PETER S · 1985 to 2021
$29.6M
GENETIC APPROACHES TO AGING RESEARCHT32AG000057 · NIA · UNIVERSITY OF WASHINGTON · PI RABINOVITCH, PETER S · 1985 to 2019
$14.2M
Diabetes, Obesity and Metabolism Training ProgramT32DK007247 · NIDDK · UNIVERSITY OF WASHINGTON · PI GREGORY J MORTON, KRISTINA Marie UTZSCHNEIDER · 1986 to 2026
$10.0M
NAD+/NADH ratio, protein acetylation and mitochondrial functionR01HL110349 · NHLBI · UNIVERSITY OF WASHINGTON · PI TIAN, RONG · 2011 to 2020
$5.7M
Quantitation of protein interactions in cancer cellsR01GM086688 · NIGMS · UNIVERSITY OF WASHINGTON · PI BRUCE, JAMES EDWARD · 2009 to 2019
$4.2M
AMP-activated protein kinase in hypertrophied heartsR01HL067970 · NHLBI · UNIVERSITY OF WASHINGTON · PI TIAN, RONG · 2001 to 2010
$3.6M
Bruker Avance III 600 MHz (14T) Wide Bore SpectrometerS10RR029021 · NCRR · UNIVERSITY OF WASHINGTON · PI KUSHMERICK, MARTIN J · 2010 to 2010
$1.0M
American Heart Association-American Stroke Association 13POST16200007NCRR NIH HHS S10 RR029021NHLBI NIH HHS R01 HL067970NHLBI NIH HHS R01 HL110349NIA NIH HHS P01 AG001751NIA NIH HHS T32 AG000057NIDDK NIH HHS T32 DK007247NIGMS NIH HHS R01 GM086688
6 · The paper itself

Abstract

backgroundImpairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction.

methodsWe assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD(+) ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD(+) pool also were tested.

resultsIncreased NADH/NAD(+) and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD(+) levels by stimulating the NAD(+) salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD(+) ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD(+) redox balance either genetically or pharmacologically.

conclusionsWe show that mitochondrial protein hyperacetylation due to NAD(+) redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD(+) imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD(+) precursors are feasible in humans.

Indexed as

AnimalsBiological TransportCalciumHeart FailureHumansMiceMitochondria, HeartMitochondrial Membrane Transport ProteinsMitochondrial Permeability Transition PoreNADOxidation-ReductionCalciumMitochondrial Membrane Transport ProteinsMitochondrial Permeability Transition PoreNADcardiac metabolismheart failurehypertrophymitochondriapermeability transition pore

Identifiers

PMID27489254
PMCPMC5193133
OpenAlexW2482233788

What OpenQuestion holds

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LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.