Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Hoshino, Atsushi; Okawa, Yoshifumi; Ariyoshi, Makoto; Kaimoto, Satoshi; Uchihashi, Motoki; Fukai, Kuniyoshi; Iwai-Kanai, Eri; Matoba, Satoaki

doi:10.1161/circheartfailure.113.001062

Cited by 59 publications

(42 citation statements)

References 40 publications

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“…Lon knockdown in yeast and human HeLa cells led to an increase in mitochondrial ROS and the accumulation of carbonylated proteins (Bayot et al, 2014). In a mouse model of pressure overload heart failure, where ATP-dependent proteolytic activity is reduced due to the oxidation of AAA+ proteases, impairment of the Lon homologue LONP1 also led to an increase in the production of ROS and carbonylated proteins in the mitochondria (Hoshino et al, 2014). This suggests a vicious cycle where protease dysfunction is associated with the increased oxidative stress and accumulation of oxidatively damaged proteins that occur in heart failure (Wang and Robbins, 2006).…”

Section: Removal Of Oxidised Proteins From the Mitochondriamentioning

confidence: 99%

Oxidised protein metabolism: recent insights

Samardzic

Rodgers

2017

Biological Chemistry

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Abstract:The 'oxygen paradox' arises from the fact that oxygen, the molecule that aerobic life depends on, threatens its very existence. An oxygen-rich environment provided life on Earth with more efficient bioenergetics and, with it, the challenge of having to deal with a host of oxygen-derived reactive species capable of damaging proteins and other crucial cellular components. In this minireview, we explore recent insights into the metabolism of proteins that have been reversibly or irreversibly damaged by oxygen-derived species. We discuss recent data on the important roles played by the proteasomal and lysosomal systems in the proteolytic degradation of oxidatively damaged proteins and the effects of oxidative damage on the function of the proteolytic pathways themselves. Mitochondria are central to oxygen utilisation in the cell, and their ability to handle oxygen-derived radicals is an important and still emerging area of research. Current knowledge of the proteolytic machinery in the mitochondria, including the ATPdependent AAA+ proteases and mitochondrial-derived vesicles, is also highlighted in the review. Significant progress is still being made in regard to understanding the mechanisms underlying the detection and degradation of oxidised proteins and how proteolytic pathways interact with each other. Finally, we highlight a few unanswered questions such as the possibility of oxidised amino acids released from oxidised proteins by proteolysis being re-utilised in protein synthesis thus establishing a vicious cycle of oxidation in cells.

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Section: Removal Of Oxidised Proteins From the Mitochondriamentioning

confidence: 99%

Oxidised protein metabolism: recent insights

Samardzic

Rodgers

2017

Biological Chemistry

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“…Lon carbonylation and tyrosine nitration are prominent in a mouse model of pressure overload heart failure after transverse aortic constriction (TAC) [82]. The measurement of ATP-dependent proteolytic activity in isolated mitochondria revealed marked reductions in mitochondrial protease activity.…”

Section: Lon Involvement In Human Diseasesmentioning

confidence: 99%

Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

Bota

Davies

2016

Free Radical Biology and Medicine

132

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The Mitochondrial Lon protease, also called LonP1 is a product of the nuclear gene LONP1. Lon is a major regulator of mitochondrial metabolism and response to free radical damage, as well as an essential factor for the maintenance and repair of mitochondrial DNA. Lon is an ATP-stimulated protease that cycles between being bound (at the inner surface of the inner mitochondrial membrane) to the mitochondrial genome, and being released into the mitochondrial matrix where it can degrade matrix proteins. At least three different roles or functions have been ascribed to Lon: 1) Proteolytic digestion of oxidized proteins and the turnover of specific essential mitochondrial enzymes such as aconitase, TFAM, and StAR; 2) Mitochondrial (mt)DNA-binding protein, involved in mtDNA replication and mitogenesis; and 3) Protein chaperone, interacting with the Hsp60–mtHsp70 complex. LONP1 orthologs have been studied in bacteria, yeast, flies, worms, and mammals, evincing the widespread importance of the gene, as well as its remarkable evolutionary conservation. In recent years, we have witnessed a significant increase in knowledge regarding Lon's involvement in physiological functions, as well as in an expanding array of human disorders, including cancer, neurodegeneration, heart disease, and stroke. In addition, Lon appears to have a significant role in the aging process. A number of mitochondrial diseases have now been identified whose mechanisms involve various degrees of Lon dysfunction. In this paper we review current knowledge of Lon's function, under normal conditions, and we propose a new classification of human diseases characterized by a either over-expression or decline or loss of function of Lon. Lon has also been implicated in human aging, and we review the data currently available as well as speculating about possible interactions of aging and disease. Finally, we also discuss Lon as potential therapeutic target in human disease.

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“…Interestingly, Deval et al found that Lon protein levels increases with age in rat hearts while overall Lon activity remains unchanged, suggesting that there is an accumulation of inactive Lon [90]. Recently, Hoshino et al reported that Lon is subject to oxidative modifications which attenuate its protease activity in failing mouse hearts [91]. Thus, these studies demonstrate that chronic stress and aging negatively affect proteins that are involved in mitochondrial quality control.…”

Section: Compromised Mitochondrial Quality Control In Aging and DImentioning

confidence: 99%

Mitochondrial quality control in the myocardium: Cooperation between protein degradation and mitophagy

Hammerling

Gustafsson

2014

Journal of Molecular and Cellular Cardiology

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Mitochondria are critical for cardiomyocyte survival and maintenance of normal cardiac function. However, changes in the extra- or intracellular environments during stress can cause excessive damage to mitochondria and lead to activation of cell death. In fact, there is evidence that mitochondrial dysfunction is an important contributor to both development of heart failure and the aging process. To counteract the adverse effects resulting from mitochondrial damage, cells have evolved mitochondrial quality control pathways that act at both the protein and organelle levels. Quality control of proteins in the outer mitochondrial membrane is monitored by the ubiquitin-protease system, whereas chaperons and proteases act in the various compartments of the mitochondria. When the damage is too excessive and the degradation machinery is overwhelmed, the entire mitochondrion is eliminated by an autophagosome. Together, these pathways ensure that myocytes maintain a functional network of mitochondria which provides ATP for contraction. Unfortunately, chronic stress and aging can negatively affects proteins that are involved in the mitochondrial quality control pathways which leads to accumulation of dysfunctional mitochondria and loss of myocytes. In this review, we provide an overview of the proteins and pathways that regulate mitochondrial quality control in the cell with an emphasis on pathways involved in maintaining protein and organelle homeostasis. We also delve into the effects of reduced mitochondrial quality control on aging and cardiovascular disease.

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Oxidative Post-Translational Modifications Develop LONP1 Dysfunction in Pressure Overload Heart Failure

Cited by 59 publications

References 40 publications

Oxidised protein metabolism: recent insights

Oxidised protein metabolism: recent insights

Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

Mitochondrial quality control in the myocardium: Cooperation between protein degradation and mitophagy

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