Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer

Abstract

Mitochondrial DNA (mtDNA), encoding 13 out of more than 1,000 proteins of the mitochondrial proteome, is of paramount importance for the bioenergetic machinery of oxidative phosphorylation that is required for tumor initiation, propagation, and metastasis. In stark contrast to the widely held view that mitochondria and mtDNA are retained and propagated within somatic cells of higher organisms, recent in vitro and in vivo evidence demonstrates that mitochondria move between mammalian cells. This is particularly evident in cancer where defective mitochondrial respiration can be restored and tumor-forming ability regained by mitochondrial acquisition. This paradigm shift in cancer cell biology and mitochondrial genetics, concerning mitochondrial movement between cells to meet bioenergetic needs, not only adds another layer of plasticity to the armory of cancer cells to correct damaged mitochondria, but also points to potentially new therapeutic approaches. Cancer Res; 75(16); 3203-8. Ó2015AACR.

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

“…Although mtDNA has been implicated in the regulation of tumor development and progression (26, 40–42), it has been challenging to dissect the precise contributions, largely because the models have been limited. Off-target effects of pharmacologic inhibitors, exposure to mutagenic agents, and challenges associated with cross-over between nuclear genomes have been raised as possible limitations for previously published studies (27, 28).…”

Mitochondrial Function in Allergic Disease

“…Studies indicate that mitochondrial exchange between cells might be a regular physiological phenomenon. Intercellular mitochondrial transfer occurs unidirectionally (mesenchymal stem cells (MSCs) -> injured lung epithelia) and bidirectionally (fibroblast <-> fibroblast, MSCs <-> fibroblasts) in the cellular milieu [78][79][80]*. It is speculated that such transfers enhance the availability of functional mitochondria in cells, supplementing the relatively slower, multistage process of mitochondrial biogenesis [79•].…”

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

“…Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including atherosclerosis (9), Alzheimer’s disease (10, 11), diabetes (12), obesity (13), aging (5), and cancer (8, 14, 15). Although the mechanisms responsible remain mostly unknown, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation, since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes.…”