Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome

Abstract

Mitochondria are complex intracellular organelles that have long been identified as the powerhouses of eukaryotic cells because of the central role they play in oxidative metabolism. A resurgence of interest in the study of mitochondria during the past decade has revealed that mitochondria also play key roles in cell signaling, proliferation, cell metabolism and cell death, and that genetic and/or metabolic alterations in mitochondria contribute to a number of diseases, including cancer. Mitochondria have been identified as signaling organelles, capable of mediating bidirectional intracellular information transfer: anterograde (from nucleus to mitochondria) and retrograde (from mitochondria to nucleus). More recently, evidence is now building that the role of mitochondria extends to intercellular communication as well, and that the mitochondrial genome (mtDNA) and even whole mitochondria are indeed mobile and can mediate information transfer between cells. We define this promiscuous information transfer function of mitochondria and mtDNA as "momiome" to include all mobile functions of mitochondria and the mitochondrial genome. Herein, we review the "momiome" and explore its role in cancer development, progression, and treatment.

Keywords: Anterograde; Cancer; Cancer prevention; Epigenetic; Exosome; Extracellular ATP; Intercellular; Mipigenetics; Mitochondria; Mitochondria-to-nucleus; Mitochondrial DNA; Nuclear mitochondria; Nucleus-to-mitochondria; Numtogenesis; Retrograde; Therapy; miRNA.

Fig. 1

Mutations in mtDNA sequence and alterations in mtDNA content have been identified in a wide variety of human cancers. These alterations are now known to trigger mitochondria-to-nucleus retrograde response (discussed in detail in text). Both somatic and germ-line mtDNA mutations have been reported in breast [32], brain [29], bladder [27], colorectal [33], head & neck [27], lung [27], ovarian [30], prostate [26, 28, 34], and thyroid [31, 35] cancers. Depletion in mtDNA has been reported in breast [47], colorectal [46], gastric [34, 46] hepatocellular [46], kidney [48, 51], lung [46], ovarian [50], and prostate [44] cancers. An increase in mtDNA content has been reported in Burkitt’s lymphoma [45], chronic lymphocytic leukemia [45], head & neck cancer [45], non-Hodgkin’s lymphoma [45], small lymphocytic lymphoma [45], and papillary thyroid carcinoma [47, 49].

Fig. 2. Information Transfer by Mobile Mitochondria and Mitochondrial Genome, aka the “Momiome”

Mitochondria have been identified as important signaling organelles which help to maintain cellular homeostasis. Alterations in signaling pathways may play a crucial role in tumorigenesis. I. Intracellular information transfer. Mitochondria are capable of mediating both anterograde (from nucleus to mitochondria) and retrograde (from mitochondria to nucleus) bidirectional intracellular information transfer. Evidence in support of these phenomena includes: the presence of nuclear genome-encoded epigenetic DNA modification machinery in mitochondria; identification of mtDNA-encoded miRNAs capable of altering nuclear gene expression; nuclear transcription factor mediated mitochondria-nuclear crosstalk; and accumulation of mtDNA in the nucleus (NUMT). II. Extracellular information transfer. During stress conditions mitochondria release their DNA and other molecules into the extracellular milieu. Extracellular release of ATP triggers different signaling mechanisms in the parent cell and/or neighboring cells that regulate tumor growth and immune cell functions. Damage-associated molecular patterns (DAMPs) can activate innate and adaptive immune responses and contribute to inflammation and the development of different human pathologies, including cancer. III. Intercellular information transfer. Mitochondria also play a crucial role in intercellular information exchange via mitochondria-derived vesicles, peptides, and exosomes, and via whole mitochondria transfer through tunneling nanotubes (TNTs) between neighboring cells.