Mitochondrial function, zinc, and intermediary metabolism relationships in normal prostate and prostate cancer

Abstract

Human prostate secretory epithelial cells have the uniquely specialized function of accumulating and secreting extremely high levels of citrate. This is achieved by their ability to accumulate high cellular levels of zinc that inhibit citrate oxidation. This process of net citrate production requires unique metabolic/bioenergetic mitochondrial relationships. In prostate cancer, the malignant cells undergo a metabolic transformation from zinc-accumulating citrate-producing sane cells to citrate-oxidizing malignant cells that lost the ability to accumulate zinc. This review describes the metabolic/bioenergetic, zinc and mitochondrial relationships involved in normal and malignant prostate. Hopefully, this report will generate much needed interest and research in this neglected, but critically important, area of investigation.

Fig. 1

The pathway of net citrate production in citrate-producing prostate epithelial cells. Aspartate provides the intramitochondrial source of oxaloacetate and glucose provides the source of acetyl CoA for citrate synthesis. Citrate oxidation is limited due to the inhibition of m-aconitase activity by the intramitochondrial accumulation of high zinc levels. Citrate accumulates within the cell and is ultimately secreted as a major constituent of prostatic fluid. asp, aspartate; gluc, glucose; glut, glutamate; OAA, oxalacetate; CoASH, coenzyme A; AcCoA, acetyl coenzyme A; isocit, isocitrate; aKG, alpha ketoglutarate; succ, succinate; mal, malate; pyr, pyruvate; lact, lactate; PDH, pyruvate dehydrogenase; CS, citrate synthase; ACON, aconitase; mAAT, mitochondrial aspartate aminotransferase; GDH, glutamic dehydrogenase.

Fig. 2

Zinc induction of mitochondrial apoptogenesis in prostate cells.

Fig. 3

Comparison of the zinc and citrate changes in prostate cancer. The citrate data are taken from Liney et al. (1997). The values were determined by in situ MRS measurements. The normal and cancer citrate values are for the peripheral zone; and the adenoma values are for the central zone. The zinc data are from Zaichick et al. (1997). The values were determined by analysis of biopsy samples.

Fig. 4

A proposed concept of the role of zinc and citrate-related energy metabolism in the pathogenesis and treatment of prostate malignancy. Normal prostate peripheral zone epithelial cells contain a transport mechanism for the accumulation of high zinc levels; represented as ZIP zinc uptake transporter. Due to zinc inhibition of citrate oxidation, these cells accumulate high levels of citrate and sacrifice the potential energy derived from citrate oxidation. The normal cell is genetically transformed to a neoplastic malignant cell type which initially is metabolically incapable of manifesting malignant activities. The neoplastic cell loses the ability to accumulate zinc and begins to exhibit the metabolic conversion to a pre-malignant citrate-oxidizing cell. Citrate oxidation proceeds with the accompanying production of ATP which provides the metabolic requirements for the full expression of malignant activities and proliferation of the malignant cells. Consequently, the pre-malignant and malignant cells will be arrested by restoration of the accumulation of zinc; or by agents which will selectively inhibit m-aconitase and citrate oxidation; or by repression of the expression of m-aconitase.