Resistance of mtDNA-depleted cells to apoptosis

Roberta Ferraresi1, Leonarda Troiano, Marcello Pinti

  • 1Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Insights

Mitochondria-lacking (rho(0)) cells show reduced apoptosis sensitivity. This resistance is linked to higher glutathione levels and increased P-glycoprotein expression, suggesting a role in multidrug resistance.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Cancer Research

Background:

  • Mitochondria-lacking (rho(0)) cells are valuable models for cancer, aging, and disease research.
  • Functional characterization of rho(0) cells, particularly regarding apoptosis, remains incomplete.

Purpose of the Study:

  • To investigate the functional differences between rho(0) cells and their parental counterparts concerning apoptosis.
  • To analyze apoptosis, mitochondrial membrane potential, reactive oxygen species, glutathione levels, and P-glycoprotein expression in rho(0) cells.

Main Methods:

  • Utilized rho(0) cell clones derived from the 143B human osteosarcoma line.
  • Treated cells with apoptogenic agents (staurosporine, doxorubicin, daunomycin, quercetin) and valinomycin.
  • Assessed apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), reduced glutathione (GSH), and P-glycoprotein (P-gp) expression (mRNA and protein).

Main Results:

  • Rho(0) cells exhibited significantly reduced sensitivity to apoptosis compared to parental cells.
  • Mitochondrial membrane potential (MMP) was stable in rho(0) cells, even after exposure to apoptogenic or depolarizing agents.
  • Rho(0) cells maintained higher reduced glutathione (GSH) levels and showed significant overexpression and enhanced functionality of P-glycoprotein (P-gp).

Conclusions:

  • Rho(0) cells display inherent resistance to apoptosis, potentially mediated by increased GSH scavenger capacity.
  • The observed hyperexpression and functionality of P-glycoprotein in rho(0) cells suggest a link to multidrug resistance.
  • These findings highlight the complex functional adaptations of rho(0) cells and their implications for disease modeling.

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.