A09: Decision between local mitophagy and neuronal cell death

Project Leader: Angelika Harbauer

Due to the elaborate morphology of neurons, their sub-compartments display heterogeneity regarding energy use, nutrient access and glucose uptake. Altered brain metabolism and insulin resistance are increasingly recognized as early events in neurodegeneration, yet it is unknown how metabolic alteration affects local mitochondrial health and global cell death decisions. We have previously identified mitochondrial co-transport of the Pink1 mRNA as an essential mechanism to allow removal of damaged mitochondria from axons. Loss of Pink1 mRNA tethering by shRNA knock down of the outer mitochondrial protein SYNJ2BP reduces neuronal viability despite functional PINK1 biogenesis in the cell body, arguing that the dysregulation of local mitophagy is sufficient to elicit cell death of the entire neuron. In this proposal we first want to understand how these neurons die and what aspect of mitochondrial function (or lack thereof) decides between cell repair mechanisms and cell death. We then want to understand how metabolic states and mitochondrial intoxication alter neuronal susceptibility to cell death inducers to further understand how mitochondrial functionality and mitophagy drive the decision between survival and cell death. This will conceptually advance our knowledge on how dietary or pharmacological interventions could skew this balance towards neuronal survival to prevent neurodegeneration.