Mg ++ requirement for MtHK binding, and Mg ++ stabilization of mitochondrial membranes via activation of MtHK & MtCK and promotion of mitochondrial permeability transition pore closure: A hypothesis on mechanisms underlying Mg ++’s antioxidant and cytopro

• Magnesium ions have anti-oxidant, anti-necrotic, and anti-apoptotic effects.
• Mg ++ ions stabilize mitochondrial membranes via their action at: MtHK, MtCK, and PTP.
• Mg ++ ions also enhance cell survival via promoting Akt protein kinase activation.
• Magnesium/Calcium Hypothesis: Ca & Mg have antagonistic effects at MtHK, MtCK, & PTP.
• Proposal: Trial of Mg supplementation for cytopathies with elevated [Ca ++/Mg ++]i

Evidence points to magnesium’s antioxidant, anti-necrotic, and anti-apoptotic effects in cardio- and neuroprotection. With magnesium being involved in over 300 biochemical reactions, the mechanisms underlying its cytoprotective and antioxidant effects have remained elusive. The profound anti-apoptotic, anabolic, and antioxidant effects of mitochondrion bound hexokinase (MtHk), and the anti-apoptotic, anti-necrotic, and antioxidant functions of mitochondrial creatine kinase (MtCK) have been established over the past few decades. As powerful regulators of the mitochondrial permeability transition pore (PTP), MtHK and MtCK promote anti-apoptosis and anti-necrosis by stabilizing mitochondrial outer and inner membranes. In this article, it is proposed that magnesium is essentially and directly involved in mitochondrial membrane stabilization via (i) Mg ++ ion requirement for the binding of mitochondrial hexokinase (ii) Mg ++’s allosteric activation of mitochondrial bound hexokinase, and stimulation of mitochondrial bound creatine kinase activities, and (iii) Mg ++ inhibition of PTP opening by Ca ++ ions. These effects of Mg ++ ions are indirectly supplanted by the stimulatory effect of magnesium on the Akt kinase survival pathway. The “Magnesium/Calcium Yin Yang Hypothesis” proposes here that because of the antagonistic effects of Ca ++ and Mg ++ ions in the presence of high Ca ++ ion concentration at MtHK, MtCK, and PTP, magnesium supplementation may provide cytoprotective effects in the treatment of some degenerative diseases and cytopathies with high intracellular [Ca ++]/ [Mg ++] ratio at these sites, whether of genetic, developmental, drug induced, ischemic, immune based, toxic, or infectious etiology.