Do Mitochondria Regulate Cellular Iron Homeostasis Through Citric Acid and Heme Production? Implications for Cancer and Other Diseases
Year: 2001
Type: preprint
Abstract: Citric acid is produced industrially by depriving Aspergyllus niger of Fe. In its desperate search for Fe, the fungus produces copious amounts of the acid (in its mitochondria), which binds to and reduces Fe3+, and is reabsorbed by the fungus. Therefore, citric acid is a powerful siderophore.The mitochondrion produces citric acid when it needs Fe in order to reproduce or to activate the citric acid cycle, which contains many Fe enzymes. On the other hand, when the mitochondrion has plenty of Fe, mitochondrial aconitase is activated and citric acid is transformed into isocitrate in the mitochondrion, which is rapidly metabolized to all the other intermediate products of the tricarboxylic acid cycle. So that no citrate leaves the mitochondrion. Likewise, cytosolic aconitase (Iron binding protein 1 or IBP-1) is also activated when there is free Fe in the cytosol, depleting the citric acid in the cytosol.Citrate probably induces the production of the mRNA encoding for IBP-1 production and for transferrin receptor (TrR). In which case, the mitochondrion would not only be a source of ATP and some crucial substances (heme, fatty acids, etc), but also the regulator of Fe homeostasis for the human cell.The mitochondrion produces heme, which it requires for cytochrome synthesis and the cell requires for the synthesis of many enzymes and hemoglobin and for the production of carbon monoxide, an important signaling agent. Heme production stops when heme levels are high or Fe levels are low. When both heme and Fe levels are low, the mitochondrion increases its production of citric acid, triggering Fe uptake. When heme levels are high, the mitochondrion stops producing it, causing an increase in Fe levels in the mitochondrion, interruption of citric acid production, a rise of Fe levels in cytosol, blocking Fe uptake.Cancer cells are smaller and have a larger nucleus, so that they have less cytoplasm and fewer mitochondria. Therefore, Fe-citrate is more likely to reach the nucleus, ensuring ample Fe supplies for rapid mitosis.
Source: SSRN Electronic Journal
Author: Simon C. Johnson
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3123691523