Mitochondrial determinants of cancer health disparities

Abstract

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. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, 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, which in turn 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 Americans 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.

Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans

“…Beyond cognitive aging, because of humanin’s role in other diseases including cardiovascular disease and diabetes, circulating levels of humanin could also contribute to additional diseases that disproportionately affect African Americans. The mitochondria have been implicated in health disparities because of their central importance in many diseases and the uniparental inheritance of the genome 46 . The role of humanin in health disparities is a novel concept that further implicates the mitochondria in the biological basis of health disparities.…”

Mitochondrial alterations may underlie race-specific differences in cancer risk and outcome

“…Koochekpour et al (7) observed mitochondrial DNA depletion in prostate tissue from African American patients and suggested that lower mitochondrial DNA content contributes to differences by race in prostate cancer incidence and progression. Additional research has focused on both germline and somatic mutations in mitochondrial DNA in prostate cancer and other malignancies with variable findings (8). Finally, use of metformin as a prostate cancer chemopreventive has shown some promise, as it has been linked to reduced risk of recurrence, metastatic disease, and death in men with concomitant type 2 diabetes (9).…”

Evaluation of the Mitochondria Respirometric Function in the Conditions of Pathologies of Various Geneses

“…наиболее энергозатратных органов, для функционирования которых необходим постоянный пул макроэргов [19,20,21]. Настоящее исследование было сосредоточено на оценке респирометрической функции митохондрий в условиях патологий ишемического генеза, при которых наблюдается существенный энергодефицит, прямо характеризующий деятельность митохондрий -фокальной ишемии, ЧМТ, инфаркте миокарда и мышечной дисфункции [22].…”