Enhanced Succinate Oxidation with Mitochondrial Complex II Reactive Oxygen Species Generation in Human Prostate Cancer

Abstract

The transformation of prostatic epithelial cells to prostate cancer (PCa) has been characterized as a transition from citrate secretion to citrate oxidation, from which one would anticipate enhanced mitochondrial complex I (CI) respiratory flux. Molecular mechanisms for this transformation are attributed to declining mitochondrial zinc concentrations. The unique metabolic properties of PCa cells have become a hot research area. Several publications have provided indirect evidence based on investigations using pre-clinical models, established cell lines, and fixed or frozen tissue bank samples. However, confirmatory respiratory analysis on fresh human tissue has been hampered by multiple difficulties. Thus, few mitochondrial respiratory assessments of freshly procured human PCa tissue have been published on this question. Our objective is to document relative mitochondrial CI and complex II (CII) convergent electron flow to the Q-junction and to identify electron transport system (ETS) alterations in fresh PCa tissue. The results document a CII succinate: quinone oxidoreductase (SQR) dominant succinate oxidative flux model in the fresh non-malignant prostate tissue, which is enhanced in malignant tissue. CI NADH: ubiquinone oxidoreductase activity is impaired rather than predominant in high-grade malignant fresh prostate tissue. Given these novel findings, succinate and CII are promising targets for treating and preventing PCa.

Zinc in Prostate Health and Disease: A Mini Review

“…Using fresh prostate cancer tissue Zhang et al, 2022 have shown that advancing prostate cancer is associated with mitochondrial complex II-dependent ROS production and impaired mitochondrial complex I oxidation, which originates from insufficient suppression of mitochondrial aconitase due to Zn deficiency [ 137 ]. Nuclear factor erythroid 2-related factor 2 (NRF2) is the master regulator for oxidative stress management, and the activation of NRF2-antioxidant responsive element pathway enhances Zn efflux from cell organelles including that of mitochondria [ 138 ].…”

The relationship between immune cells and prostate cancer, and the mediating role of metabolites: a Mendelian randomization study

“…When carbohydrate intake is low or during fasting, the liver produces ketone bodies such as acetoacetic acid and hydroxybutyric acid. Evidence suggests that serum pyruvate levels increase in PCa [40,41],and that pyruvate levels are linked to PCa progression and metastasis [42][43][44]. Studies have found that the activity level of acetyl-CoA transferase expressed in human breast cancer and rat liver cancer is related to the rate of tumor growth, and the level of acetoacetic acid also increases accordingly [45].…”

Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer

“…Over the past few years, enhanced succinate oxidation by SDH has been identified as an emergent hallmark of PCa metabolism [9][10][11] . Increased reliance on succinate in response to reduced Complex I (CI) activity is also not unique to cancer, as cell-permeable succinate has been shown to overcome CI dysfunction in models of mitochondrial disease 34 .…”

“…The remodelling of oxidative phosphorylation (OxPhos) has recently been identified as a key characteristic of high-grade prostate cancer tissue. Specifically, these studies describe a metabolic shift from NADH-linked respiration to succinate-linked respiratory function (SLRF) 9,10 . Increased SLRF in high-grade PCa tissue is also coincident with a heightened burden of heteroplasmic mitochondrial DNA (mtDNA) mutations 11 .…”