Do mitochondria regulate cellular iron homeostasis through citric acid and haem production? Implications for cancer and other diseases

Med Hypotheses. 2003 Jan;60(1):106-11. doi: 10.1016/s0306-9877(02)00342-0.


Citric acid is produced industrially by depriving Aspergillus niger of iron. The lack of Fe deactivates mitochondrial aconitase and interrupts the krebs cycle, causing the mitochondria to release citric acid as a siderophore (an Fe getter). When the mitochondrion has plenty of Fe and the cell has enough ATP, aerobic phosphorylation stops and fatty acid or haem synthesis take place, when the cell has plenty of haem, haem synthesis stops. Since most of the Fe activity in the cell is related to the mitochondria, I hypothesise that in the animal cell when the mitochondria are low in Fe, citric acid acts as a signal that triggers the production of transferrin receptor messenger RNA (TrR mRNA) in the nucleus, which in the absence of Fe causes the expression of transferrin receptor. When the cell has plenty of Fe, cytosolic aconitase detaches itself from the transferrin receptor and ferritin mRNA stopping expression of the former and initiating expression of the latter. The detached cytosolic aconitase transforms the citric acid, blocking the production of the transferrin receptor mRNA.

MeSH terms

  • Blood Platelets / metabolism
  • Citric Acid / metabolism
  • Heme / metabolism
  • Homeostasis
  • Humans
  • In Vitro Techniques
  • Iron / metabolism*
  • Mitochondria / metabolism*
  • Models, Biological
  • Neoplasms / etiology
  • Neoplasms / metabolism
  • Neoplasms / therapy


  • Citric Acid
  • Heme
  • Iron