A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

Lai, Ling; Wang, Miao; Martin, Ola J.; Leone, Teresa C.; Vega, Rick B.; Han, Xianlin; Kelly, Daniel P.

doi:10.1074/jbc.m113.523654

Cited by 82 publications

(74 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…15 Recently, PGC-1α/β were also described as cardiolipin synthesis modulators. 16 These data are in accordance with our results showing that doxorubicin-treated males displayed almost normal in vitro mitochondrial protein content and activity, whereas in situ oxidative capacity are reduced probably because of altered cardiolipin environment of the respiratory chain.…”

Section: Discussionsupporting

confidence: 82%

“…Because AMPK and more recently PGC-1α/β have been shown to regulate cardiolipin homeostasis, the cardiolipin content was measured. 15,16 A strong reduction was revealed only in doxorubicin-treated males ( Figure 6B). Mitochondrial biogenesis and cardiolipin environment emerged as other key sites of doxorubicin-related sex differences because there is a significant statistical interaction between sex and treatment effects (Table I in the Data Supplement).…”

Section: Doxorubicin Severely Impairs Mitochondrial Biogenesis In Malesmentioning

confidence: 99%

See 1 more Smart Citation

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

114

View full text Add to dashboard Cite

Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Doxorubicin Severely Impairs Mitochondrial Biogenesis In Malesmentioning

confidence: 99%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

114

View full text Add to dashboard Cite

show abstract

“…We additionally investigated whether SLN mediated increase in mitochondrial biogenesis involves Ca 2ϩ dependent signaling pathways, especially the CAMKII and calcineurin/NFAT pathway (23)(24)(25)(26)(27). We found an increased expression of CamkII (and its target Gsk3b) as well as calcineurin (and its target Nfam1) (Fig.…”

Section: Sln Increases the Mitochondrial Biogenesis And Oxidativementioning

confidence: 99%

Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity

Maurya

Bal

Sopariwala

et al. 2015

Journal of Biological Chemistry

138

140

View full text Add to dashboard Cite

Background: Sarcolipin (SLN), a regulator of SR Ca 2ϩ ATPase (SERCA) in muscle, can promote the uncoupling of SERCA from Ca 2ϩ transport and increase heat production. Results: Overexpression of SLN in muscle increases energy expenditure and provides resistance against diet-induced obesity. Conclusion: SLN plays a role in whole-body metabolism. Significance: SLN can serve as novel target to increase energy expenditure in muscle.

show abstract

“…Surprisingly, cardiac-specific, inducible deletion of Ppargc1b on a systemic Ppargc1a-null background in adult mice results in a rather minimal mitochondrial structural phenotype without overt cardiac dysfunction. However, the hearts of these mice exhibit a marked and global reduction in expression of nuclear-encoded mitochondrial genes and reduced State 3 respiration (71,76). Compared with the neonatal phenotype, the minimal cardiac phenotype of adult PGC-1α/β deficiency may reflect relatively low rates of mitochondrial turnover and replacement (mitophagy) in the normal adult heart.…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

“…In addition, although cardiac-specific inactivation of both PGC-1α and -1β in the adult heart does not lead to overt dysfunction, it does produce abnormalities in phospholipid biosynthesis that may impair mitochondrial function. Mice lacking both cardiac PGC-1α and -1β contain mitochondria that display a phenotype reminiscent of mitochondria found in patients with Barth syndrome, a rare genetic disorder caused by the inability to produce mature cardiolipin (76). Indeed, Ppargc1a/b-knockout mice have reduced cardiolipin and impaired mitochondrial respiration.…”

Section: Energy Metabolic Derangements In the Failing Heartmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

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...

show abstract

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

Cited by 82 publications

References 45 publications

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity

Cardiac nuclear receptors: architects of mitochondrial structure and function

Contact Info

Product

Resources

About