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][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...

Defects of the respiratory chain in hepatic oncocytes

“…Age-related defects of the respiratory chain have also been described in other tissues, especially the skeletal muscle including limb, external eye muscles and diaphragm [47,51,54] and also in the heart and the substantia nigra [32,46]. In a recent study similar defects were also found in normal and cirrhotic livers [55].…”

“…This is characterized by a decreased respiratory rate for various substrates, a decrease in respiratory control (quotient of ADP-stimulated/unstimulated respiration) and a significant lowering of phosphorylation rate. In earlier investigations we were able to demonstrate that defects of complex III and especially of complex IV were found with increasing frequency during normal ageing of the liver and in cirrhosis, the defect area being significantly larger in cirrhotic than in normal livers [55].…”

“…The tissues were fixed in formalin (10%), embedded in paraffin and routinely stained with haematoxilin-eosin, Prussian blue for iron detection and elastica-van Gieson stain. In the livers defects of cytochrome-c-oxidase, the terminal enzyme of the respiratory chain [35], were detected by immunohistochemistry in an earlier study [55]. Cytochrome-c-oxidase is composed of 13 subunits, the largest (I-III) of which are encoded by mitochondrial DNA (mtDNA).…”

The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease

“…Such damage to mitochondrial DNA appears to be heterogeneous in ageing tissues [55]. Whether this damage to individual mtDNA genomes causes the cell to lose mitochondrial function has been a controversial area, although it is known that there are heterogeneous losses of mitochondrial enzyme activities in muscle and liver tissues in aged animals, whilst liver cells removed from old animals show a heterogeneous loss of mitochondrial membrane potential [56][57][58].…”

Strokes in mitochondrial diseases

“…Отмечаются задержка физического и полового развития, ихтиоз с очагами гиперпигментации, вальгусная девиация голеней и высокий свод стопы. Нарушения со стороны эндокринной системы -дефицит гормона роста, гипогонадизм, сахарный диабет, гипопаратиреоз, наруше-ние адреналового обмена [63,66,[72][73][74][75][76][77][78][79][80].…”