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

Abstract

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 11-17 have revealed that aging is an inhomogeneous process at the cellular level leading to randomly dis-where 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 differ-the 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 pathogene-respiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) sis of mitochondrial diseases. 19-22 Similar mutations also accumulate with age although at a lesser degree both in hu-had 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. 39-47 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. ties in microdissected respiratory chain defective liver cell MATERIALS AND METHODS areas. Single point mutations at nt 3243 and/or 5692 were found only in 7 of 18 microdissected probes from 6 patients. Investigations were performed on the following: 1) 107 resection specimens of ...

Locating the stem cell niche and tracing hepatocyte lineages in human liver

“…These observations are entirely consistent with a previous study that found an age-related increase in frequency of cytochrome c oxidase-deficient patches in human liver, but no increase in overall size; moreover, there was no consistent genetic abnormality between patches, suggesting a stochastic process, such as free radical damage. 27 Overall, these observations are consistent with cytochrome c oxidase deficiency accruing over time in long-lived cells (stem cells), that eventually become recognized histologically, thus giving rise to similarly deficient progeny (recognized as patches of cytochrome c oxidase-deficient hepatocytes). In the human gut, crypts with cytochrome c oxidase deficiency are not seen before approximately 40 years of age, again consistent with a lengthy time for a stem cell to acquire a histologically detectable deficiency in cytochrome c oxidase.…”

Abnormal hepatic energy homeostasis in type 2 diabetes

“…51 Because the majority of this group is older than 50 years, aging-induced mitochondrial damage could contribute to the observed alterations of phosphorus metabolites in our T2DM individuals. Reduced energy metabolism could be due to loss of functional hepatocytes or reduction of mitochondrial contents and/or fitness.…”

Aging Liver

“…Caloric restriction (CR) can decrease enzymatic capacity for glycolysis and increase the enzymatic capacity for hepatic gluconeogenesis and the disposal of byproducts of muscle protein catabolism [20]. Hormonal inducibility of mitochondrial enzymes is reduced and respiratory chain enzymes can decrease with aging [21].…”