Abstract
In mammalian species, mitochondrial DNA (mtDNA) with pathogenic mutations that induce mitochondrial respiration defects has been proposed to be involved in tumor phenotypes via induction of enhanced glycolysis under normoxic conditions (the Warburg effects). However, because both nuclear DNA and mtDNA control mitochondrial respiratory function, it is difficult to exclude the possible contribution of nuclear DNA mutations to mitochondrial respiration defects and the resultant expression of tumor phenotypes. Therefore, it is important to generate transmitochondrial cybrids sharing the same nuclear DNA background but carrying mtDNA with and without the mutations by using intercellular mtDNA transfer technology. Our previous studies isolated transmitochondrial cybrids and showed that specific mtDNA mutations enhanced tumor progression as a consequence of overproduction of reactive oxygen species (ROS). This study assessed whether mtDNA mutations inducing ROS overproduction always enhance tumor progression. We introduced mtDNA from senescence-accelerated mice P1 (SAMP1) into C57BL/6J (B6) mice-derived Lewis lung carcinoma P29 cells, and isolated new transmitochondrial cybrids (P29mtSAMP1 cybrids) that overproduced ROS. The inoculation of the cybrids into B6 mice unexpectedly showed that mtDNA from SAMP1 mice conversely induced tumor suppression. Moreover, the tumor suppression of P29mtSAMP1 cybrids in B6 mice occurred as a consequence of innate immune responses of the host B6 mice. Enzyme pretreatment experiments of P29mtSAMP1 cybrids revealed that some peptides encoded by mtDNA and expressed on the cell surface of P29mtSAMP1 cybrids induce increased IL-6 production from innate immune cells (dendritic cells) of B6 mice, and mediate augmented inflammatory responses around the tumor-inoculated environment. These observations indicate presence of a novel role of mtDNA in tumor phenotype, and provide new insights into the fields of mitochondrial tumor biology and tumor immunology.
Highlights
Mammalian mitochondrial DNA with pathogenic mutations that induce significant mitochondrial respiration defects causes mitochondrial diseases [1,2]
Because P29mtSAMP1 cybrids demonstrated reactive oxygen species (ROS) overproduction (Figure 1B), we examined whether mitochondrial DNA (mtDNA) mutations that induce ROS overproduction always enhance tumor progression, as we proposed in our previous study [8]
Taken together with our previous observation [9], these results suggest that some mtDNA mutations function as tumor suppressors (Figure 1C), while the other mtDNA mutations function as tumor enhancers [9], even though they both induce ROS overproduction
Summary
Mammalian mitochondrial DNA (mtDNA) with pathogenic mutations that induce significant mitochondrial respiration defects causes mitochondrial diseases [1,2]. It has been hypothesized that pathogenic mutations in mtDNA may contribute to aging and age-associated disorders via overproduction of reactive oxygen species (ROS) [1,2,3,4]. This hypothesis, the so-called mitochondrial theory of aging, is partly supported by studies in mtDNA mutator mice, which possess a nuclear-encoded mtDNA polymerase with a defective proofreading function, resulting in enhanced expression of respiration defects with age and the subsequent expression of premature aging phenotypes [5,6,7]. We generated such transmitochondrial cybrids [8,9] and transmitochondrial mito-mice [10,11] and showed that specific mtDNA mutations regulated tumor progression as a consequence of their induction of ROS overproduction while they did not regulate aging phenotypes [11]
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