Mitochondrial determinants of cancer health disparities

Abstract

Mitochondria, which are multi-functional, have been implicated in cancer initiation, progression, and metastasis due to metabolic alterations in transformed cells. Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Due to maternal inheritance and ethnic-based diversity, the mitochondrial genome (mtDNA) contributes to inherited racial disparities. In people of African ancestry, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, all of which can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African population and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

Keywords: African American; Anterograde; Cancer diversity; Cancer prevention; Cancer therapy; Caucasian; Disparity; Epigenetic; Exosome; Genomic instability; Mipigenetics; Mitochondria; Mitochondria-to-nucleus; Mitochondrial DNA; Nuclear mitochondria; Numtogenesis; Racial; Retrograde.

Figure 1. mtDNA and nDNA encode subunits comprising the OXPHOS complexes

mtDNA encodes 13 protein subunits involved in OXPHOS complexes; the other OXPHOS subunits are encoded by nDNA.

Figure 2. mtDNA alterations associated with cancer disparity

Three non-synonymous and tRNA substitutions are identified in epidemiologic studies as being associated with an increased risk of cancer in specific populations. G10398A in ND3 is associated with increased risk of breast (OR=1.6) and prostate cancer (OR=19.8) in AAs. A12308G in tRNA^Leu2 is a marker of the mtDNA haplogroup U. In Caucasians, this haplogroup is associated with increased risk of prostate (OR=1.95) and renal cancer (OR=2.52).^* In isolation, the T4216C substitution in ND1 confers no increased risk. However, when the T4216C substitution is present with G10398A, the risk of breast cancer is increased (OR=3.1) in AAs. Further, mtDNA depletion is reported to be associated with cancer disparities for AAs.

Figure 3. Differences in mipigenetic mechanisms may contribute to cancer disparity

Schematic depiction of mechanisms probably involved in cancers induced by mitochondrial dysfunction. Mitochondrial dysfunction or suboptimal function can arise due to mutations or variants in genes involved in nuclear genes encoding the mitochondrial proteome or mitochondrial genes encoding the OXPHOS. See text and Figure 2 for variants described in AAs, Caucasian Americans, and other ethnic populations. A transient mitochondrial dysfunction turns on the mitocheckpoint control to restore the normal mitochondrial function. Restoration involves intergenomic mipigenetic cross talk at epigenetic (e.g., DNA methylation) and genetic levels (gene expression). A severe mitochondrial dysfunction may result in cellular senescence, leading to apoptosis and mitochondrial diseases. A persistent mitochondrial dysfunction arising due to mutations in either nuclear or mitochondrial genes can cause senescence and result in genetic instability in the nuclear genome as well as resistance to apoptosis, underlying tumorigenic cell transformation, and development of cancer.