PMID- 28030582
OWN - NLM
STAT- MEDLINE
DCOM- 20170718
LR  - 20181231
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 12
DP  - 2016
TI  - Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide 
      Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity.
PG  - e0168283
LID - 10.1371/journal.pone.0168283 [doi]
LID - e0168283
AB  - Mitochondrial dysregulation is closely associated with excessive reactive oxygen 
      species (ROS) production. Altered redox homeostasis has been implicated in the 
      onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and 
      proteins are particularly sensitive to ROS as they are in close proximity to the 
      respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, 
      selectively damages breast cancer cells possibly through damage induced via 
      enhanced ROS production. However, the effects of MitoQ and other 
      triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis 
      remain unknown. The primary objective of this study was to determine the impact 
      of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, 
      mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA 
      integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of 
      the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy 
      number, as well as by measuring mitochondrial proteins essential to mtDNA 
      stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial 
      status was evaluated by measuring superoxide production, mitochondrial membrane 
      depolarization, oxygen consumption, extracellular acidification and mRNA or 
      protein levels of the RC complexes along with TCA cycle activity. In this study, 
      we demonstrated that all investigated MTAs impair mitochondrial health and 
      decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the 
      degree of mitochondrial damage and mtDNA degradation suggest unique properties 
      among each MTA that may be cell line, dose and time dependent. Collectively, our 
      study indicates the potential for TPP+ conjugated molecules to impair breast and 
      lung cancer cells by targeting mitochondrial homeostasis.
FAU - Pokrzywinski, Kaytee L
AU  - Pokrzywinski KL
AD  - Laboratory of Applied Biochemistry, Division of Biotechnology Research and Review 
      III, Office of Biotechnology Products, Center for Drug Evaluation and Research, 
      U.S. Food and Drug Administration, Silver Spring, Maryland, United States of 
      America.
FAU - Biel, Thomas G
AU  - Biel TG
AD  - Laboratory of Applied Biochemistry, Division of Biotechnology Research and Review 
      III, Office of Biotechnology Products, Center for Drug Evaluation and Research, 
      U.S. Food and Drug Administration, Silver Spring, Maryland, United States of 
      America.
FAU - Kryndushkin, Dmitry
AU  - Kryndushkin D
AD  - Laboratory of Applied Biochemistry, Division of Biotechnology Research and Review 
      III, Office of Biotechnology Products, Center for Drug Evaluation and Research, 
      U.S. Food and Drug Administration, Silver Spring, Maryland, United States of 
      America.
FAU - Rao, V Ashutosh
AU  - Rao VA
AD  - Laboratory of Applied Biochemistry, Division of Biotechnology Research and Review 
      III, Office of Biotechnology Products, Center for Drug Evaluation and Research, 
      U.S. Food and Drug Administration, Silver Spring, Maryland, United States of 
      America.
LA  - eng
PT  - Journal Article
DEP - 20161228
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Organophosphorus Compounds)
RN  - 11062-77-4 (Superoxides)
RN  - 1339-63-5 (Ubiquinone)
RN  - 47BYS17IY0 (mitoquinone)
SB  - IM
MH  - Breast Neoplasms/drug therapy/genetics/*pathology
MH  - DNA, Mitochondrial/genetics
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/drug therapy/genetics/*pathology
MH  - Mitochondria/drug effects/*genetics/*pathology
MH  - Mitochondrial Membranes/metabolism
MH  - Mitochondrial Proteins/metabolism
MH  - Organophosphorus Compounds/*pharmacology
MH  - Oxidation-Reduction
MH  - Oxidative Stress
MH  - Small Cell Lung Carcinoma/drug therapy/genetics/*pathology
MH  - Superoxides/*metabolism
MH  - Ubiquinone/*analogs & derivatives/pharmacology
PMC - PMC5193408
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/12/29 06:00
MHDA- 2017/07/19 06:00
PMCR- 2016/12/28
CRDT- 2016/12/29 06:00
PHST- 2016/09/02 00:00 [received]
PHST- 2016/11/29 00:00 [accepted]
PHST- 2016/12/29 06:00 [entrez]
PHST- 2016/12/29 06:00 [pubmed]
PHST- 2017/07/19 06:00 [medline]
PHST- 2016/12/28 00:00 [pmc-release]
AID - PONE-D-16-35301 [pii]
AID - 10.1371/journal.pone.0168283 [doi]
PST - epublish
SO  - PLoS One. 2016 Dec 28;11(12):e0168283. doi: 10.1371/journal.pone.0168283. 
      eCollection 2016.