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

被引:119
作者
Bota, Daniela A. [1 ,2 ]
Davies, Kelvin J. A. [3 ,4 ]
机构
[1] UC Irvine Sch Med, Dept Neurol, 200 S Manchester Ave,Suite 206, Orange, CA 92868 USA
[2] UC Irvine Sch Med, Chao Family Comprehens Canc Ctr, 200 S Manchester Ave,Suite 206, Orange, CA 92868 USA
[3] Ethel Percy Andrus Gerontol Ctr, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA
[4] Univ Southern Calif, Dept Biol Sci, Div Mol & Computat Biol, Dornsife Coll Letters Arts & Sci, Los Angeles, CA 90089 USA
基金
美国国家卫生研究院;
关键词
Lon; Proteolysis; Mitochondria; Mitochondrial DNA; Aging; Cancer; Mitochondrial diseases; Neurodegeneration; ATP-DEPENDENT PROTEASE; AMYOTROPHIC-LATERAL-SCLEROSIS; BOVINE ADRENAL-CORTEX; RAT-LIVER MITOCHONDRIA; CAUSES CELL-DEATH; CANCER-CELLS; OXIDATIVE STRESS; CODAS SYNDROME; UP-REGULATION; TRANSCRIPTION FACTOR;
D O I
10.1016/j.freeradbiomed.2016.06.031
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Mitochondrial Lon protease, also called LonP1 is a product of the nuclear gene LONPI. 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 Hsp60mtHsp70 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. (C) 2016 Elsevier B.V. All rights reserved.
引用
收藏
页码:188 / 198
页数:11
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