The mitochondrial permeability transition pore (mPTP) seems to be a critical final common path to cell injury and death in multiple disease states. Discovered in the 1970’s by Hunter and Haworth, the critical trigger for pore opening is an excess of calcium in the mitochondrial matrix, while oxidative or nitrosative stress lower the threshold for calcium induced pore opening. Once the large conductance pore in the inner mitochondrial membrane has opened, the membrane potential will collapse causing depletion of ATP, mitochondria swell and – if the whole population of mitochondria in a cell undergo permeability transition –cell death. Critically, pore opening can be limited pharmacologically, making the pore a potential therapeutic target for multiple diseases (for a recent review, see (1)).  

I will talk about a disease in which a pathophysiological cascade seems to involve opening of the mPTP probably in a subset of mitochondria with more complex but critical consequences.  Vici syndrome is an apparently rare devastating early onset multisystem disorder caused by mutations of a protein known as EPG5, which plays a key role in autophagy, mediating fusion specificity of the autophagosome and lysosome. Almost every system is involved in Vici syndrome but in addition to multiple developmental defects, neurological and neuromuscular features are most prominent.  Affected children suffer from a progressive neurodegeneration that, in combination with severe cardiorespiratory involvement, is usually fatal by the age of 10 at the severe end of the disease spectrum. 

In fibroblasts from children with EPG5 mutations, mitophagy is significantly impaired². We have found that, as a consequence, mitochondria are profoundly dysfunctional, with impaired respiration and reduced mitochondrial membrane potential. In exploring the impact of a calcium signal on mitochondrial function in these cells, we were surprised to find that mitochondrial calcium uptake was paradoxically significantly increased.  This was attributable to downregulation of MICU1, the Ca²⁺ dependent gatekeeper of mitochondrial calcium uptake. As a consequence, mitochondria from these cells show an increased vulnerability to mPTP opening in response to normally innocuous calcium signals. This is followed by release of mtDNA into the cytosol which activates the cGAS/STING pathway, initiating the innate inflammatory response. It seems probable that this response plays a significant role in shaping the disease presentation and progression, especially in relation to the neurodegenerative disorder. These data point to multiple steps at which therapeutic intervention might prove beneficial – pharmacological stimulation of mitophagy, reducing mitochondrial calcium overload, inhibition of the mPTP or inhibition of the cGAS/STING pathway.