Mitohormesis, UPRmt, and the Complexity of Mitochondrial DNA Landscapes in Cancer

Abstract

The discovery of the Warburg effect, the preference of cancer cells to generate ATP via glycolysis rather than oxidative phosphorylation, has fostered the misconception that cancer cells become independent of the electron transport chain (ETC) for survival. This is inconsistent with the need of ETC function for the generation of pyrimidines. Along with this misconception, a large body of literature has reported numerous mutations in mitochondrial DNA (mtDNA), further fueling the notion of nonfunctional ETC in cancer cells. More recent findings, however, suggest that cancers maintain oxidative phosphorylation capacity and that the role of mtDNA mutations in cancer is likely far more nuanced in light of the remarkable complexity of mitochondrial genetics. This review aims at describing the various model systems that were developed to dissect the role of mtDNA in cancer, including cybrids, and more recently mitochondrial-nuclear exchange and conplastic mice. Furthermore, we put forward the notion of mtDNA landscapes, where the surrounding nonsynonymous mutations and variants can enhance or repress the biological effect of specific mtDNA mutations. Notably, we review recent studies describing the ability of some mtDNA landscapes to activate the mitochondrial unfolded protein response (UPR^mt) but not others. Furthermore, the role of the UPR^mt in maintaining cancer cells in the mitohormetic zone to provide selective adaptation to stress is discussed. Among the genes activated by the UPR^mt, we suggest that the dismutases SOD2 and SOD1 may play key roles in the establishment of the mitohormetic zone. Finally, we propose that using a UPR^mt nuclear gene expression signature may be a more reliable readout than mtDNA landscapes, given their diversity and complexity.

Figure 1.. Cellular and animal models to study the role of mtDNA in cancer

A. Transmitochondrial cytoplasmic hybrid (Cybrid) technology. Cells with nuclear DNA of interest (nDNA A) have mtDNA depleted to generate ρ⁰ cells. Cells with mitochondrial DNA of interest (mtDNA B) are enucleated to generate an mtDNA donor. ρ⁰ and the mtDNA are fused to generate a cybrid with nDNA A and mtDNA B. MNX mice are generated by enucleating the oocytes of inbred mouse strains (Strain A and B, oocytes A and B). Nuclei from these oocytes are exchanged into opposite oocytes generating oocyte X with mtDNA A and nDNA B and oocyte Y with mtDNA B and nDNA A. These oocytes are placed in psuedopregnant females to generated MNX strains X and Y. C. Conplastic mice are generated by the continual backcrossing of females with mtDNA of interest (mtDNA A) to male mice with nDNA of interest (nDNA B) for at least 10 generations until conplastic mice are generated with mtDNA A and nDNA B. (modified from LES LABORATOIRES SERVIER)™ available under a Creative Commons 3.0 Unported License.

Figure 2.. The mitochondrial unfolded protein response, mitohoremsis, and mtDNA landscape complexity in cancer.

A. The mammalian mitochondrial unfolded protein response (UPR^mt). Different axes of the UPR^mt are activated in parallel by perturbations to mitochondrial stress leading to collective mito-protective outcomes. B. Dose response curve of a mitohormetic response to a given stressor or toxin (i.e. ROS). At low levels of toxin/stressor, within the hormetic zone, positive biological responses are seen – such as activation of the UPR^mt. At higher doses, negative biological responses are seen. C. Within the primary tumor, UPR^mt negative (−) and positive (+) populations can be identified. UPR^mt+ populations are characterized by mitohormesis and show increased invasive and metastatic capacities. D. The role of SOD1, a member of the UPR^mt, in cancer. Oncogenic transformation of a normal cell results in the increase of reactive oxygen species (ROS). In the absence of SOD1, tumor formation is blocked. SOD1 inhibition selectively kills established cancer cells. E. Levels of complexity of mtDNA landscapes in cancer. Level 1 of complexity is the mtDNA haplotype with its unique set of variants and mutations. Level 2 of complexity is the acquistion of a driving mtDNA mutation in cancer. This mutation will manifest differently given the mtDNA haplotype in which it resides. Level 3 of complexity is the additional variants and mutants gained. These additional mtDNA differences can act as modifiers of both the driving mutation and the mtDNA haplotype. Level 4 of complexitiy is heteroplasmy. The heteroplasmic frequencies of each driving mutation and modifier variants/mutations will also impact the effect of mtDNA on cancer. We propose that cancer cells will select mtDNA landscapes that activate the UPR^mt to promote primary tumor formation and metastasis. (modified from LES LABORATOIRES SERVIER)™ available under a Creative Commons 3.0 Unported License.