Changes in the rat liver mitochondrial DNA upon aging

Asano, Kimiko; Amagase, Shizuko; Matsuura, Etsuko T.; Yamagishi, Hideo

doi:10.1016/0047-6374(91)90040-7

Cited by 20 publications

(4 citation statements)

References 23 publications

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“…This property appears to be because of firmly associated proteins. 125 patic respiratory chain function with age may predispose to decreased hepatic adaptive responsiveness as proposed by Using specific probes for different regions of mtDNA it was also found that the content of mtDNA relative to nuclear the late Hans Popper 65 in normal and especially in cirrhotic livers under conditions of increased stress such as infections, DNA decreases remarkably during aging. 126 [H 3 ]thymidine labeling studies suggest a lowered replication of mtDNA but circulatory failure, exogenic liver damage or liver resection.…”

Section: Aidmentioning

confidence: 97%

Defects of the respiratory chain in the normal human liver and in cirrhosis during aging

et al. 1997

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cal studies of the respiratory chain complexes in these and Defects of the respiratory chain are a typical feature of mitochondrial diseases and occur also during normal aging other tissues [11][12][13][14][15][16][17] have revealed that aging is an inhomogeneous process at the cellular level leading to randomly diswhere they have been described in postmitotic tissues. The present study addresses the question of defect expression in tributed defects of cytochrome-c-oxidase (complex IV of the respiratory chain) and to intercellular and interorgan differthe normal and cirrhotic liver. Randomly distributed defects of complex III (ubiquinone-cytochrome-c-oxidoreductase) and ences of the defect manifestation.Recently a decline of respiratory rates with age was also of complex IV (cytochrome-c-oxidase) of the respiratory chain have been detected with age-related increasing frequency both reported for the human liver 18 both for unstimulated (state 4) and adenosine diphosphate-stimulated respiration (state in normal and cirrhotic livers. No defects were present for complex II (succinate-dehydrogenase) and complex V (adeno-3). In the last few years molecular genetic studies have revealed that mutations of mitochondrial DNA (mtDNA) such sine triphosphate-synthase) and in liver cell carcinomas. Sixty-one of 107 normal livers (57%) showed defects of the as deletions, duplications, point mutations in transfer RNAs (tRNAs), and structural genes are involved in the pathogenerespiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) sis of mitochondrial diseases. [19][20][21][22] Similar mutations also accumulate with age although at a lesser degree both in huhad defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving mans 23-38 and in animals. [39][40][41][42][43][44][45][46][47] The present study reports on a random defect pattern of the respiratory chain in normal and both nuclearly and mitochondrially coded subunits. Ninetyfour percent of the defects (n Å 275) involved complex IV cirrhotic livers during aging underlining that aging occurs primarily at the individual cellular level and that similar selectively. In 4% selective defects of complex III were found and combined defects of both complexes occurred in only pathogenetic mechanisms are involved in postmitotic fixed muscular tissue and in liver. Although the random defect 2%. In situ hybridization and polymerase chain reaction (PCR) studies for the detection of the common deletion (4.977 bp) pattern favors a stochastic process, molecular genetic analyses failed to reveal a pathogenetic role of various mutations and of various point mutations of mitochondrial DNA (mtDNA) revealed no consistent molecular genetic abnormali-of mtDNA. Loss of respiratory chain function is a typical feature of normal livers and to the 8th decade in patients with cirrhosis. The mitochondrial diseases. 1-3 To a lesser degree respiratory chain tissue probes were stored fr...

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Section: Aidmentioning

confidence: 97%

Defects of the respiratory chain in the normal human liver and in cirrhosis during aging

et al. 1997

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“…By use of the nuclear repetitive LINE sequence as an internal standard, Asano and coworkers (121,122) demonstrated that the mtDNA/nuclear DNA ratio decreases in the liver and heart muscle of the rat. Pertruzzella and coworkers (120) used a DNA probe specific to the D-loop region of mtDNA to measure the content of mtDNA of rat brain tissues by Southern hybridization.…”

Section: Age-related Depletion Of Mitochondria1 Dnamentioning

confidence: 99%

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Wei¹

1998

Experimental Biology and Medicine

329

197

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The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the "Mitochondrial theory of aging."

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“…Several recent reviews have focussed on age-associated oxidative damage and mtDNA mutations (26,27). Support for this hypothesis comes from several sources: 1) the existence of numerous, potentially pathogenic mtDNA deletions in a variety of aged tissues (26,27); 2) aging-dependent functional alterations of mtDNA from human fibroblasts transferred into mtDNA-less cells (28); and 3) the decline in the activity of several critical mitochondrial enzymes in human muscle with advancing age (29)(30)(31)(32). However, the dilemma regarding causality remains, leading investigators to examine the phenotypic and functional consequences of oxidative injury, and specifically mitochondrial abnormalities, in which to delineate the intermediate steps leading to cellular aging.…”

Section: Evidence For Oxidative Damagementioning

confidence: 99%

Aging: Is Oxidative Stress a Marker or Is It Causal?

Fukagawa

1999

Proc Soc Exp Biol Med

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Rapid developments in free radical biology and molecular technology have permitted exploration of the free radical theory of aging. Oxidative stress has also been implicated in the pathogenesis of a number of diseases. Studies have found evidence of oxidative damage to macromolecules (DNA, lipids, protein), and data in transgenic Drosophila melanogaster support the hypothesis that oxidative injury might directly cause the aging process. Additional links between oxidative stress and aging focus on mitochondria, leading to development of the mitochondrial theory of aging. However, despite the number of studies describing the association of markers of oxidative damage with advancing age, few, if any definitively link oxidative injury to altered energy production or cellular function. Although a causal role for oxidative stress in the aging process has not been clearly established, this does not preclude attempts to reduce oxidative injury as a means to reduce morbidity and perhaps increase the healthy, useful life span of an individual. This review highlights studies demonstrating enhanced oxidative stress with advancing age and stresses the importance of the balance between oxidants as mediators of disease and important components of signal transduction pathways.

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Changes in the rat liver mitochondrial DNA upon aging

Cited by 20 publications

References 23 publications

Defects of the respiratory chain in the normal human liver and in cirrhosis during aging

Defects of the respiratory chain in the normal human liver and in cirrhosis during aging

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Aging: Is Oxidative Stress a Marker or Is It Causal?

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