Figure 1.

Synopsis of mitochondrial dynamics and turnover in neuronal models of TSC. TSC is a prototypical MTORopathy and a genetically-tractable model that enables us to study the downstream consequences of a constitutive activation of MTORC1 in neurons. Using a variety of methods in neuronal models of TSC, including induced pluripotent stem cell-derived neurons from TSC patients and neuron-specific Tsc1 knockout mice, we were able to show that loss of TSC1/2 leads to impaired mitophagy both in the axon and cell body. This leads to an increase in mitochondrial mass and mitochondrial dysfunction signified by mitochondrial fragmentation as well as loss of the mitochondrial membrane potential and respiratory chain capacity in a significant subset of organelles. In the axon, retrograde transport of mitochondria is enhanced, which contributes to a progressive depletion of mitochondria from axons including from presynaptic sites.