AMP- Activated Protein Kinase (AMPK) Activation for the Treatment of Mitochondrial Disease

There are multiple copies of mtDNA per cell and each mtDNA molecule contains the information to encode 13 electron transport chain (ETC) proteins. When mtDNA is depleted, there is a decrease in ETC activity. 5' AMP-activated protein kinase (AMPK) is a kinase that can initiate mitochondrial biogenesis and mitophagy. We hypothesized that treating cells harbouring low numbers of mtDNA with an AMPK activator (5-Aminoimidazole-4-carboxamide ribonucleoside; AICAR) would ameliorate the decrease in ETC activity and improve mtDNA copy number. We developed myoblasts (C2C12 cells) depleted of mtDNA with long-term ethidium bromide treatment. We treated selected clones for 24 hours with 1 mM AICAR to activate AMPK. AICAR treatment decreased markers of mitochondrial biogenesis, mitochondrial function (e.g. maximal cellular respiration), and mitochondrial degradation. Thus, failing to increase the energy producing capacity of the cell, activation of AMPK may have induced an energy sparing mechanism.