Defective DNA Replication Impairs Mitochondrial Biogenesis In Human Failing Hearts

Karamanlidis, Georgios; Nascimben, Luigino; Couper, Gregory S.; Shekar, Prem; Monte, Federica del; Tian, Rong

doi:10.1161/circresaha.109.212753

Cited by 205 publications

(184 citation statements)

References 38 publications

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“…An additional known target of AMPK, estrogen-related receptor α (ERRα) expression (26), was also decreased in banded Chip -/-hearts (Supplemental Figure 3C). ERRα regulates mitochondrial biogenesis independently of PGC1-α (26,27), and our observation of decreased ERRα and PGC1-α expression is consistent with reduced AMPK function and decreased mitochondrial biogenesis in banded Chip -/-hearts. These results indicate that, despite allosteric cues (increased ADP/ ATP ratio) and increased expression of LKB1, AMPK activation and activity are significantly diminished in banded Chip -/-hearts, suggesting that either proteins regulated by CHIP or CHIP itself plays a key role in AMPKα activation and activity toward downstream targets during cardiac pressure overload.…”

Section: Figuresupporting

confidence: 86%

CHIP protects against cardiac pressure overload through regulation of AMPK

Schisler

Rubel²,

Zhang³

et al. 2013

J. Clin. Invest.

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Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in Chip -/-mice resulted in robust hypertrophy and decreased cardiac function and energy generation stemming from a failure to activate AMPK. Mechanistically, CHIP promoted LKB1-mediated phosphorylation of AMPK, increased the specific activity of AMPK, and was necessary and sufficient for stress-dependent activation of AMPK. CHIP-dependent effects on AMPK activity were accompanied by conformational changes specific to the α subunit, both in vitro and in vivo, identifying AMPK as the first physiological substrate for CHIP chaperone activity and establishing a link between cardiac proteolytic and metabolic pathways. IntroductionPathological cardiac hypertrophy (subsequently referred to as cardiac hypertrophy) is an adaptive response to increased afterload brought about by hypertension, decreased arterial compliance, and other cardiac stressors (1). During the development of cardiac hypertrophy, numerous cellular processes come into play, including protein synthesis and proteolysis to account for the structural changes that accompany hypertrophy, as well as changes in cardiac metabolism to cope with increased energy demands. Despite the well-known fact that protein turnover and metabolic changes accompany cardiac hypertrophy, surprisingly little is known about how stress-dependent protein quality control mechanisms and metabolic regulation are coordinated, if at all, in the heart. C terminus of HSC70-interacting protein (CHIP, also known as STUB1) is a 35-kDa cytosolic protein initially identified in a screen for proteins that interact with the mammalian chaperones HSC70, HSP70 (2), and HSP90 (3). CHIP is ubiquitously expressed in mammalian tissues but is expressed at highest levels in the adult heart (2). CHIP plays an important dual role as both a cochaperone and a ubiquitin ligase (2-5). More recently, however, an additional role for CHIP in protein quality control has been suggested. Evidence that CHIP can act as an autonomous chaperone, independent of its association with HSPs, has been reported (6). However, these observations were made with a nonphysiological substrate (luciferase), and, to date, verification of CHIP's chaperone activity and identification of a physiological substrate have not been made.Changes in cardiac metabolism, such as oxidative substrate preference, mitochondrial function, and biogenesis, play a key role in the adaptive response to cardiac stress (7). As cardiomyocyte hypertrophy progresses, energy demand increases and cellu-

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Section: Figuresupporting

confidence: 86%

CHIP protects against cardiac pressure overload through regulation of AMPK

Schisler

Rubel²,

Zhang³

et al. 2013

J. Clin. Invest.

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“…Indeed, Ppargc1a/b-knockout mice have reduced cardiolipin and impaired mitochondrial respiration. Third, a number of studies in animal models and in humans have shown reduced levels of PGC-1α and ERR transcripts and protein levels in heart failure (117)(118)(119)(120)(121). Collectively, these data clearly connect diminished mitochondrial respiration capacity with reduced ERR/PGC-1 signaling and suggest that this may be a final common pathway in heart failure ( Figure 3).…”

Section: Energy Metabolic Derangements In the Failing Heartmentioning

confidence: 85%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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“…In the failing ventricular myocard from patients with end-stage heart failure a marked decline in mitochondrial Mn-SOD protein and activity is detected [138]. Mitochondrial biogenesis is also severely impaired as evidenced by reduced mtDNA replication and depletion of mtDNA in the human failing heart [139].…”

Section: Mitochondrial Ros Production and Angiotensin II In Cardiac Fmentioning

confidence: 99%

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

Lijnen¹

2011

TOHYPERJ

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Angiotensin II increases the NAD(P)H-dependent superoxide anion production and the intracellular generation of reactive oxygen species in cardiac fibroblasts and apocynin, a NAD(P)H oxidase inhibitor, abrogates this rise. The membrane associated NAD(P)H oxidase complex is the predominant source of superoxide anion and reactive oxygen species generation in angiotensin II-stimulated adult cardiac fibroblasts. Inhibition of this NAD(P)H oxidase complex with apocynin completely blocks the angiotensin II-stimulated collagen production, collagen I and III protein and mRNA expression.Superoxide anion production is also increased by the Cu,Zn-superoxide dismutase (SOD) inhibitor diethyldithiocarbamic acid (DETC) and decreased by the superoxide scavenger tempol in control and ANG II-treated fibroblasts. ANG II and DETC stimulate the collagen production and the collagen I and fibronectin content in fibroblasts. The SOD mimetics tempol and EUK-8 as well as polyethyleneglycol-SOD reduce the collagen production.ANG II also decreases the activity and mRNA and protein expression of the mitochondrial antioxidants Mn-SOD and peroxiredoxin-3. Upon phosphorylation of Akt by ANG II, P-Akt is translocated from the cytoplasm to the nucleus and nuclear phosphorylation of FOXO3a by P-Akt leads to relocalisation of FOXO3a from the nucleus to the cytosol, resulting in a decrease in its transcriptional activity and in Mn-SOD expression. These data indicate that ANG II inactivates FOXO3a by activating Akt and this leads to a reduction in the expression of the antioxidant Mn-SOD. A role of SOD and the formed reactive oxygen species in the regulation and organization of collagen in cardiac fibroblasts is suggested.

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Defective DNA Replication Impairs Mitochondrial Biogenesis In Human Failing Hearts

Cited by 205 publications

References 38 publications

CHIP protects against cardiac pressure overload through regulation of AMPK

CHIP protects against cardiac pressure overload through regulation of AMPK

Cardiac nuclear receptors: architects of mitochondrial structure and function

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

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