Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells

Abstract

Mitochondrial respiratory function is impaired in the target tissues of patients with mitochondrial diseases and declines with age in various human tissues. It is generally accepted that respiratory-chain defects result in enhanced production of reactive oxygen species and free radicals in mitochondria. Recently, we have demonstrated that the copy number of mitochondrial DNA (mtDNA) is increased in the lung tissues of elderly human subjects. The mtDNA copy number was suggested to be increased by a feedback mechanism that compensates for defects in mitochondria harbouring mutated mtDNA and a defective respiratory system. However, the detailed mechanism remains unclear. In this study, we treated a human lung fibroblast cell line, MRC-5, with H(2)O(2) at concentrations of 90-360 microM. After the treatment for 24-72 h, we found that cells were arrested at G(0) and G(1) phases but that mitochondrial mass and mtDNA content were significantly increased in a concentration- and time-dependent manner. Moreover, the oxidative stress induced by buthionine sulphoximine was also found to cause an increase in mitochondrial mass of the treated cells. Increased uptake of a vital mitochondrial dye Rhodamine 123 and enhanced tetrazolium [MTT, 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] reduction revealed that the mitochondria increased by H(2)O(2) treatment were functional. In addition, the increase in the mitochondrial mass was also observed in cell-cycle-arrested cells induced by mimosine, lovastatin and genistein. Taken together, these findings suggest that the increase in mitochondrial mass and mtDNA content are the early molecular events of human cells in response to endogenous or exogenous oxidative stress through cell-cycle arrest.

BGP-15 Protects against Oxaliplatin-Induced Skeletal Myopathy and Mitochondrial Reactive Oxygen Species Production in Mice

“…The net effect of OXA treatment at the mitochondrial level was increased succinate dehydrogenase (SDH) content within the muscle, indicative of a greater mitochondrial oxidative capacity. However, there was a trend for OXA ( p = 0.07) to reduce mitochondrial viability relative to VEH (Figure 8C), highlighting that the innate response to oxidative stress and/or mitochondrial toxicity is to increase the total pool to preserve energy production capacity (Hsin-Chen et al, 2000) as indicated by more intense SDH staining (Figure 6C) and mitochondrial density (Figure 8C). Consistent with this finding, a marked increase in mtROS production was detected in FDB fibers following OXA treatment (Figure 8B) giving further support to our theory that mitochondrial biogenesis could be increased in order to accommodate oxidative stress and a dysfunctional mitochondrial population (Hsin-Chen et al, 2000; Kujoth et al, 2005; Stowe and Camara, 2009; Sorensen et al, 2016).…”

“…However, there was a trend for OXA ( p = 0.07) to reduce mitochondrial viability relative to VEH (Figure 8C), highlighting that the innate response to oxidative stress and/or mitochondrial toxicity is to increase the total pool to preserve energy production capacity (Hsin-Chen et al, 2000) as indicated by more intense SDH staining (Figure 6C) and mitochondrial density (Figure 8C). Consistent with this finding, a marked increase in mtROS production was detected in FDB fibers following OXA treatment (Figure 8B) giving further support to our theory that mitochondrial biogenesis could be increased in order to accommodate oxidative stress and a dysfunctional mitochondrial population (Hsin-Chen et al, 2000; Kujoth et al, 2005; Stowe and Camara, 2009; Sorensen et al, 2016). Remarkably, BGP-15 completely protected against the OXA-induced increase in mtROS production and reduction in FDB fiber diameter and intramuscular protein content, however, this effect was independent from any modulation of protein synthesis, atrophy, autophagy or apoptosis markers measured in our study (Figure 9).…”

Occupational exposure to particles and mitochondrial DNA - relevance for blood pressure

“…The mtDNA synthesis can be stimulated by mild oxidative stress, resulting in an increase of mtDNA copy number to supply energy for cell survive, while immoderate oxidative stress may lead to decrease in mtDNA synthesis because of defect mitochondria and result in apoptosis and cell death [30, 35]. Since the median particle concentration in our study (1.1 mg/m 3 ) is not very high (the occupational exposure limit is set as 5 mg/m 3 by the Swedish Work Environment Authority [28]), we concluded that the increase in RmtDNAcn could be a feedback response to compensate defect mitochondria with an impaired respiratory chain, or mutated mtDNA caused by oxidative damage from welding fume [18, 35]. The methylation level change in the D-loop could be another molecular event related to particle induced oxidative stress, which can damage methylation of nucleotides [36].…”

“…The copy numbers of mtDNA vary in each mitochondrion, as well as in different cells, different tissues and individuals. Alteration of mtDNA copy number has been observed as a response to oxidative stress in vitro and in vivo [18–20]. Moreover, integrity of the mitochondrial genome can affect mitochondrial function [21].…”

Upregulation of Mitochondrial Gene Expression in PBMC from Convalescent SARS Patients

“…Despite the inconsistent reports, oxidative stress caused by mitochondria is shown to be involved in the regulation of mitochondrial transcription and proliferation with complicated compensatory mechanism (34)(35)(36). In SARS, both pathogen and host factors are considered to be important for the pathogenesis (9).…”