Mitochondrial DNA abnormalities provide mechanistic insight and predict reactive oxygen species-stimulating drug efficacy

Abstract

Background Associations between mitochondrial genetic abnormalities (variations and copy number, i.e. mtDNAcn, change) and elevated ROS have been reported in cancer compared to normal cells. Since excessive levels of ROS can trigger apoptosis, treating cancer cells with ROS-stimulating agents may enhance their death. This study aimed to investigate the link between baseline ROS levels and mitochondrial genetic abnormalities, and how mtDNA abnormalities might be used to predict cancer cells’ response to ROS-stimulating therapy. Methods Intracellular and mitochondrial specific-ROS levels were measured using the DCFDA and MitoSOX probes, respectively, in four cancer and one non-cancerous cell lines. Cells were treated with ROS-stimulating agents (cisplatin and dequalinium) and the IC50s were determined using the MTS assay. Sanger sequencing and qPCR were conducted to screen the complete mitochondrial genome for variations and to relatively quantify mtDNAcn, respectively. Non-synonymous variations were subjected to 3-dimensional (3D) protein structural mapping and analysis. Results Our data revealed novel significant associations between the total number of variations in the mitochondrial respiratory chain (MRC) complex I and III genes, mtDNAcn, ROS levels, and ROS-associated drug response. Furthermore, functional variations in complexes I/III correlated significantly and positively with mtDNAcn, ROS levels and drug resistance, indicating they might mechanistically influence these parameters in cancer cells. Conclusions Our findings suggest that mtDNAcn and complexes I/III functional variations have the potential to be efficient biomarkers to predict ROS-stimulating therapy efficacy in the future.

Remodeling tumor microenvironment with natural products to overcome drug resistance

“…Cancer cells tend to possess high levels of adaptive antioxidant system and highly reactive oxygen species (ROS), and increased levels of reactive oxygen species disrupt the initial redox homeostasis, which promotes tumor proliferation, metastasis and drug resistance ( 71 , 72 ). Although high ROS levels can induce apoptosis of cancer cells, their prolonged activation inevitably reduces the efficacy of chemotherapy due to the establishment of drug resistance ( 73 , 74 ). Combination therapies to combat chemotherapy resistance have been extensively studied in clinical trials, while cancer treatment strategies that modulate ROS to modify the tumor microenvironment urgently need more in-depth research ( 75 ).…”

Energetic metabolic reprogramming in Jurkat DFF40-deficient cancer cells

“…Our laboratory recently demonstrated that DFF40 deficiency in Jurkat T cells induced a higher redox state at basal state [8]. Recently, it was shown that elevated ROS production in cancer cells was associated with higher mtDNA copy number (mtDNAcn) [19]. These results brought our laboratory to suggest a role of DFF40 in preserving mitochondria homeostasis and function.…”

“…deficient Jurkat cells had higher ROS production at basal state [8]. Recently, it was shown that Caco-2 cancer cells exhibiting higher ROS production at basal state had higher mtDNAcn [19]. We thus sought to determine the impact of DFF40 deficiency in Jurkat and HeLa cells on mtDNAcn and mitochondrial mass (Fig.…”

Plumbagin Suppresses Growth, Induces Apoptosis, and Inhibits Migration in Cholangiocarcinoma via Reactive Oxygen Species Generation and Mitochondrial Function

“…Mitochondria is membrane-bound cell organelles that are considered a primary intracellular site of ROS generation, importantly, the high levels of ROS can trigger apoptosis, which is what triggers mitochondrial abnormalities. 22, 23 Plumbagin data on pancreatic cancer cells showed that it activated apoptosis through the induction of ROS production along with upregulation of cleaved caspase 3 and caspase 9 and downregulation of Bcl-2 protein. 24 The caspase cascade is the key signaling pathway that triggered apoptosis.…”