Mitochondrion as a Target for Heart Failure Therapy　– Role of Protein Lysine Acetylation –

Lee, Chi Fung; Tian, Rong

doi:10.1253/circj.cj-15-0742

Cited by 35 publications

(24 citation statements)

References 121 publications

(79 reference statements)

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“…The coordinated action of the respiratory chain complexes is dependent on their organization into functional units called respirasomes by the membrane phospholipid, cardiolipin (Szeto, 2014). Dissociation of the respirasomes leads to increased ROS generation and reduced ATP production (Lee & Tian, 2015;Rosca & Hoppel, 2013).…”

Section: Ketone Metabolismmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are associated with high morbidity and mortality. Although many established pharmacological interventions exist for HFrEF, hospitalization and death rates remain high, and for those with HFpEF (approximately half of all heart failure patients), there are no effective therapies. Recently, the role of impaired cardiac energetic status in heart failure has gained increasing recognition with the identification of reduced capacity for both fatty acid and carbohydrate oxidation, impaired function of the electron transport chain, reduced capacity to transfer ATP to the cytosol, and inefficient utilization of the energy produced. These nodes in the genesis of cardiac energetic impairment provide potential therapeutic targets, and there is promising data from recent experimental and early-phase clinical studies evaluating modulators such as carnitine palmitoyltransferase 1 inhibitors, partial fatty acid oxidation inhibitors and mitochondrial-targeted antioxidants.Metabolic modulation may provide significant symptomatic and prognostic benefit for patients suffering from heart failure above and beyond guideline-directed therapy, but further clinical trials are needed.

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Section: Ketone Metabolismmentioning

confidence: 99%

Cardiac metabolism — A promising therapeutic target for heart failure

Noordali

Loudon

Frenneaux

et al. 2018

Pharmacology & Therapeutics

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“…Targeting mitochondria for heart failure therapy has long been sought; however, previous work focusing on improving mitochondrial energy production and reducing reactive oxygen species yielded few successful clinical applications 5 . In recent years, protein lysine acetylation emerged as an important mechanism linking mitochondrial metabolism to cellular pathologies 6–8 . The level of protein acetylation reflects the balance of acetylation and deacetylation.…”

mentioning

confidence: 99%

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

et al. 2016

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Background heart failure has become increasingly prevalent along with the aging population and the increased survival of acute ischemic heart events. Impairments of mitochondrial function in the heart are intricately linked to the development of heart failure but there is no therapy for mitochondrial dysfunction in the clinic. Methods and Results we report that NAD+ redox imbalance (increased NADH/NAD+) and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, are also present in human failing hearts as well as in mouse hearts with pathological 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 ATP 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. Conclusions we show that mitochondrial protein hyperacetylation due to NAD+ redox imbalance contributes to the pathological remodeling of the heart via two 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 pharmacological strategy of increasing NAD+ precursors are feasible in human.

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“…Recent developments suggest that mitochondrial protein lysine acetylation (LysAc) modulates the sensitivity of the heart to stress and is involved in mitochondrial dysfunction and the development of heart failure [reviewed in (112)]. Myocardial acetylproteomics revealed that extensive mitochondrial protein lysine hyperacetylation occurs in the early stages of heart failure in the mouse TAC heart and in end-stage failing human heart, in association with reduced catalytic function in succinate dehydrogenase A and complex II-derived respiration (113), suggesting the role of LysAc in mitochondrial dysfunction as the primary metabolic remodeling of heart failure.…”

Section: Epigenetics and Mitochondriamentioning

confidence: 99%

Multiple Levels of PGC-1α Dysregulation in Heart Failure

Oka

Sabry

Cawley

et al. 2020

Front. Cardiovasc. Med.

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Metabolic adaption is crucial for the heart to sustain its contractile activity under various physiological and pathological conditions. At the molecular level, the changes in energy demand impinge on the expression of genes encoding for metabolic enzymes. Among the major components of an intricate transcriptional circuitry, peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) plays a critical role as a metabolic sensor, which is responsible for the fine-tuning of transcriptional responses to a plethora of stimuli. Cumulative evidence suggests that energetic impairment in heart failure is largely attributed to the dysregulation of PGC-1α. In this review, we summarize recent studies revealing how PGC-1α is regulated by a multitude of mechanisms, operating at different regulatory levels, which include epigenetic regulation, the expression of variants, post-transcriptional inhibition, and post-translational modifications. We further discuss how the PGC-1α regulatory cascade can be impaired in the failing heart.

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Mitochondrion as a Target for Heart Failure Therapy　– Role of Protein Lysine Acetylation –

Cited by 35 publications

References 121 publications

Cardiac metabolism — A promising therapeutic target for heart failure

Cardiac metabolism — A promising therapeutic target for heart failure

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

Multiple Levels of PGC-1α Dysregulation in Heart Failure

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Mitochondrion as a Target for Heart Failure Therapy – Role of Protein Lysine Acetylation –

Cited by 35 publications

References 121 publications

Cardiac metabolism — A promising therapeutic target for heart failure

Cardiac metabolism — A promising therapeutic target for heart failure

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

Multiple Levels of PGC-1α Dysregulation in Heart Failure

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Resources

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Mitochondrion as a Target for Heart Failure Therapy　– Role of Protein Lysine Acetylation –

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