Numtogenesis as a mechanism for development of cancer

Abstract

Transfer of genetic material from cytoplasmic organelles to the nucleus, an ongoing process, has implications in evolution, aging, and human pathologies such as cancer. The transferred mitochondrial DNA (mtDNA) fragments in the nuclear genome are called nuclear mtDNA or NUMTs. We have named the process numtogenesis, defining the term as the transfer of mtDNA into the nuclear genome, or, less specifically, the transfer of mitochondria or mitochondrial components into the nucleus. There is increasing evidence of the involvement of NUMTs in human biology and pathology. Although information pertaining to NUMTs and numtogenesis is sparse, the role of this aspect of mitochondrial biology to human cancers is apparent. In this review, we present available knowledge about the origin and mechanisms of numtogenesis, with special emphasis on the role of NUMTs in human malignancies. We describe studies undertaken in our laboratory and in others and discuss the influence of NUMTs in tumor initiation and progression and in survival of cancer patients. We describe suppressors of numtogenesis and evolutionary conserved mechanisms underlying numtogenesis in cancer. An understanding the emerging field of numtogenesis should allow comprehension of this process in various malignancies and other diseases and, more generally, in human health.

Figure. 1. Nuclear Mitochondria

Electron micrograph of a malignant melanoma of the choroid, showing well preserved mitochondria as nuclear inclusions (× 8960). Reproduced from the British Journal of Ophthalmology, 1980, 64: 456. Reprinted with permission from BMJ Publishing Group Ltd.

Figure 2. NUMT distribution in human chromosomes

A scale representation of the human chromosomes. The location of human-specific NUMTs is indicated with vertical bars (Adopted from Simone et al., 2011).

Figure 3. Probable mechanism(s) underlying numtogenesis

Mitostress by an intracellular or extracellular agent (numtogen) may lead to dysfunctional mitochondria, which, if not removed by mitophagy, may result in transfer of mitochondria and/or mtDNA-induced numtogenesis and tumor development.