Aging of the liver: age-associated mitochondrial damage in intact hepatocytes.
Mitochondrial damage may be a major cause of cellular aging. So far, this hypothesis had only been tested using isolated mitochondria. The aim of this study was to investigate the involvement of mitochondria in aging using whole liver cells and not isolated mitochondria only. Using flow cytometry, we found that age is associated with a decrease in mitochondrial membrane potential (30%), an increase in mitochondrial size, and an increase in mitochondrial peroxide generation (23%). Intracellular peroxide levels were also increased. The number of mitochondria per cell and inner mitochondrial membrane mass did not change. Gluconeogenesis from glycerol or fructose (mitochondrial-independent) did not change with age, whereas it did from lactate (mitochondrial-dependent). The change in the rate of gluconeogenesis was not accompanied by changes in any of the following parameters: phosphoenolpyruvate carboxykinase or pyruvate carboxylase activities or mitochondrial ATP/ADP or cytosolic NADH/NAD+ ratios. This was caused by a decreased rate of malate export (to 20% of the controls) from mitochondria. The impairment of the mitochondrial malate transporter is posttranscriptional because its expression in Xenopus oocytes using polyadenylated RNA from livers of young or old animals did not change. Ketogenesis from oleate also fell in hepatocytes from old rats. Our results show, for the first time in intact cells, a correlation between age-associated impairment of cell metabolism and specific changes in mitochondrial function and morphology, supporting the hypothesis that mitochondrial damage plays a key role in aging.
Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Spain.
J
J
Sastre
F V
FV
Pallardó
R
R
Plá
A
A
Pellín
G
G
Juan
J E
JE
O'Connor
J M
JM
Estrela
J
J
Miquel
J
J
Viña
D000375:Aging / Q000378:metabolism*; D000818:Animals; D005943:Gluconeogenesis; D008099:Liver / Q000166:cytology*; D008293:Malates / Q000378:metabolism; D008297:Male; D008563:Membrane Lipids / Q000032:analysis; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000378:metabolism*; D010545:Peroxides / Q000032:analysis; D010730:Phosphoenolpyruvate Carboxylase / Q000378:metabolism; D011766:Pyruvate Carboxylase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000378:metabolism
D008293:Malates; D008563:Membrane Lipids; D010545:Peroxides; C030298:malic acid; D014508:Urea; D010730:Phosphoenolpyruvate Carboxylase; D011766:Pyruvate Carboxylase