Formation of elongated giant mitochondria in DFO‐induced cellular senescence: Involvement of enhanced fusion process through modulation of Fis1

Abstract

Enlarged or giant mitochondria have often been documented in aged tissues although their role and underlying mechanism remain unclear. We report here how highly elongated giant mitochondria are formed in and related to the senescent arrest. The mitochondrial morphology was progressively changed to a highly elongated form during deferoxamine (DFO)-induced senescent arrest of Chang cells, accompanied by increase of intracellular ROS level and decrease of mtDNA content. Interestingly, under exposure to subcytotoxic doses of H 2 O 2 (200 mM), about 65% of Chang cells harbored elongated mitochondria with senescent phenotypes whereas ethidium bromide (EtBr) (50 ng/ml) only reformed the cristae structure. Elongated giant mitochondria were also observed in TGF b1-or H 2 O 2 -induced senescent Mv1Lu cells and in old human diploid fibroblasts (HDFs). In all senescent progresses employed in this study Fis1 protein, a mitochondrial fission modulator, was commonly downexpressed. Overexpression of YFP-Fis1 reversed both mitochondrial elongation and appearance of senescent phenotypes induced by DFO, implying its critical involvement in the arrest. Finally, we found that direct induction of mitochondrial elongation by blocking mitochondrial fission process with Fis1-DTM or Drp1-K38A was sufficient to develop senescent phenotypes with increased ROS production. These data suggest that mitochondrial elongation may play an important role as a mediator in stress-induced premature senescence.

Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

“…The findings are in good agreement with our previous study that ATP level is decreased and the cell growth is arrested after deferoxamine treatment due to the limited complex II activity and mitochondria elongation [9,50]. To examine whether the lower energy charge regulated Ran distribution in cellular senescence or not, young HDF cells were treated with antimycin A, and the result showed significant inhibition of ATP generation and subsequent loss of RanGTP in the nuclei of the cells in 30 min to 2 h of the treatment (Fig.…”

“…3). The data are in good support of our earlier studies that cell cycle delay in the senescence-associated growth arrest is due to the limited complex II activity and mitochondrial dysfunction [9,50].…”

“…induced senescence, whereas inhibition of cell growth prevents cellular senescence when the cell cycle is blocked by DNA damage and p21 WAF1 [6]. We earlier reported that globular actin (G-actin) accumulates in nuclei of the replicatively senescent human diploid E X P E R I M E N T A L C E L L R E S E A R C H 3 1 7 ( 2 0 1 1 ) 9 4 1 -9 5 4 fibroblasts (HDF) and induced senescence of cancer cells by treatment with either H 2 O 2 , deferoxamine, TGF-β1 or over expression of H-Ras double mutants [7][8][9].…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…Different cultured cells, including neurons, under oxidative stress due to NO or H 2 O 2 treatment showed extensive mitochondrial network fragmentation and increased cell death (Barsoum et al, 2006;Yoon et al, 2006;Jahani-Asl et al, 2007;Jendrach et al, 2008). Although the precise mechanisms by which oxidative stress modulates mitochondrial dynamics are not well understood, some authors suggested that ROS could modulate the expression levels and post-traslational modifications of the proteins involved in mitochondrial dynamics.…”

Nicotinamide-induced Mitophagy

“…The knockdown of mitochondrial fission results in the retention of elongated mitochondria, persistence of high ROS level, and progression into a stage of senescence (11). Exposure to H 2 O 2 or disruption of ETC function, both of which induce senescence, also causes a reduction in mitochondrial fission activity and formation of elongated or giant mitochondria (12).…”