Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways
Authors: Yiqun Zhang
Tin-Lap Lee
Yewei Ma
Lee-Jun C Wong
Benny Abraham Kaipparettu
Chad J Creighton
Jun Hyoung Park
Wai-Yee Chan
Patricia Yotnda
Journal: PloS one (2013)
Discipline: Multidisciplinary
Keywords: Mitochondrial-nucleus cross talk; Mitochondrial retrograde regulation; Transmitochondrial cybrid systems; Mitochondrial DNA variations; Oncogenic properties
Affiliations: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. 

Abstract:  Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non-cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- ρ0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDA-MB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK(-) cell including cell proliferation, viability under hypoxic condition, anti-apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy. 

Retracted: No

PubPeer comments:
 August 2019 correction, which reads: *There are errors in Fig 1E. The panels for Core 2 (complex III) and for F1u03b1 (complex V) are incorrect. A duplicate of the Ip (complex II) panel was used in error for Core 2 (complex III). Bands showing Core 2 (complex III) were used in error for F1u03b1 (complex V). The authors apologize for these errors. A corrected Fig 1 in which replacement band images are taken from the original experiment is provided here.* *The underlying blot images for Fig 1E are provided below as Supporting Information, along with the underlying data for the charts in Fig 1 as summary mean and SD. For Fig 1E, complexes II, III, and V were analyzed in a single gel, along with a u03b2-actin loading control, which was analyzed in the same blot after stripping and re-blotting. The Core 2 (complex III) panel used a higher exposure than the other panels. ND6 and u03b2-actin were analyzed in the same blot, along with porin which was analyzed in the same blot after stripping and re-blotting.* *Fig 4 reports the results of a microarray experiment. The raw data for the microarray experiment are deposited at GEO, accession GSE128610. The underlying data for other parts of the article are not available at the time of publication of this notice.* Here is the original Figure 1E with the duplication marked with red boxes. ![file] ,