Increase in Mitochondrial Mass in Human Fibroblasts under Oxidative Stress and during Replicative Cell Senescence

Abstract

Abnormal proliferation of mitochondria generally occurs in muscle of aged individuals and patients with mitochondrial myopathy. An increase in the mitochondrial DNA (mtDNA) copy number has also been observed in aging human tissues. However, the molecular mechanism underlying the increase in mitochondrial mass and mtDNA is still unclear. In a previous study, we demonstrated that sublethal levels of oxidative stress caused an increase in mitochondrial mass in human lung cells. In this communication, we report our recent findings that the mitochondrial mass in human lung fibroblasts (MRC-5) in a later proliferation stage is significantly increased compared to that in the early stages of proliferation. The extent of the increase in mitochondrial mass in the senescent cells was similar to that in cells in the early stages of proliferation that had been treated with low concentrations (≤180 µM) of hydrogen peroxide (H₂O₂). Moreover, we found that the rate of reactive oxygen species (ROS) production was higher in cells in the later proliferation stage compared to cells in the early proliferation stages. A similar phenomenon was also observed in cells in the early proliferation stages under low levels of oxidative stress. On the other hand, the mRNA levels of many nuclear DNA-encoded proteins involved in mitochondrial biogenesis, particularly nuclear respiratory factor-1, were found to increase in cells in later proliferation stages and in cells in early proliferation stages that had been treated with 180 µM H₂O₂. Interestingly, the increase in mitochondrial mass in the cells under oxidative stress could be repressed by treatment with cycloheximide or m-chlorocarbonyl cyanide phenylhydrazone but not by chloramphenicol. Furthermore, the mitochondrial mass of mtDNA-less ρ^o cells was also significantly increased by exposure to low concentrations (e.g. 180 µM) of H₂O₂. These results suggest that the increase in mitochondrial mass in replicative senescent cells may result from an increase in ROS production, and that it is dependent on both de novo synthesis of nuclear DNA-encoded proteins and their import into mitochondria, dictated by the membrane potential of mitochondria.

A new activating role for CO in cardiac mitochondrial biogenesis

“…The loss of mitochondrial H 2 O 2 disrupted Akt activation, NRF1 phosphorylation and its binding to the Tfam promoter, events that can be regulated by H 2 O 2 ). This role of mitochondrial H 2 O 2 is also consistent with the ability of exogenous peroxides to increase cell mitochondrial mass (Lee et al, 2002;.…”

Single Nucleotide Polymorphisms of PPARD in Combination With the Gly482Ser Substitution of PGC-1A and the Pro12Ala Substitution of PPARG2 Predict the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes

“…What could be the mechanisms via which acarbose modifies the effect of SNPs of PPARD and PGC-1A on the risk of diabetes? Postprandial hyperglycemia and high FFAs contribute to the production of reactive oxygen species (16,21), which increase mitochondrial mass, mainly by overexpression of nuclear respiratory factors and PGC-1␣ (22). Both acarbose and PGC-1␣ have a protective effect on reactive oxygen species formation, either by alleviating postprandial hyperglycemia and high FFAs or by transcriptionally regulating the mitochondrial antioxidant defense system (23).…”

Is defective electron transport at the hub of aging?

“…Mild oxidant challenge to human lung fibroblast cultures hastens replicative senescence and stimulates mitochondrial biogenesis (mtDNA copy number, mRNA, transcription factors) to meet the energy needs for survival. At high oxidant levels, however, genes are down-regulated as a prelude to apoptosis and cell death (Lee et al, 2002b).…”