JCB_201604065 815..834

Mitochondria are key contributors to the etiology of a wide array of diseases with neuromuscular defects or neurodegeneration (DiMauro and Schon, 2008; Nunnari and Suomalainen, 2012). Mutations within genes encoding proteins that are essential for oxidative phosphorylation (OXP HOS) cause primary mitochondrial diseases with severe neuronal deficits (Koopman et al., 2012). Mitochondrial dysfunction is also closely associated with neurodegenerative disorders, including Parkinson’s disease (PD; Itoh et al., 2013; Haelterman et al., 2014). Tissues from patients and model animals show a range of mitochondrial dysfunction–related features, including mitochondrial fragmentation, mislocalization of mitochondria, and loss of respiratory enzyme activities (Wallace and Fan, 2009; Greaves et al., 2012). Mitochondrial dysfunction in these diseases and their models results in a variety of neuropathological events, including neuronal loss, axonal degeneration, and dendritic pathology (Patt et al., 1991; Cheng et al., 2010). Although it is commonly accepted that high energy demands in neurons render the nervous system vulnerable to mitochondrial dysfunction, how the disturbance in cellular energy supply impacts cellular energy requiring processes in neurons and causes each neuropathological event is unclear (Pathak et al., 2013). Because mitochondria play a pivotal role in energetic metabolism, mitochondrial malfunction often causes changes in energy-related indicators (such as [ATP], [ATP/AMP], and [NAD+/NAD]; Nunnari and Suomalainen, 2012). The changes can act as cellular signals that directly affect signaling components, including the ATP-dependent potassium channel, the proteasome, AMPK, and sirtuins (Ying, 2008; Huang et al., 2010; Hardie et al., 2012; Tanaka et al., 2014). Consequently, these signaling events will alter diverse cellular activities, such as translocation of ions across membranes and synthesis and degradation of proteins, which may contribute to the etiology of neuronal diseases. However, the relationships between these indicators and neuronal phenotypes are still unclear. Another major conundrum in the field of mitochondriarelated diseases is how mitochondrial dysfunction leads to cellular subtype-specific pathologies of the diseases. Differential vulnerabilities in neuronal subpopulations are common in both mitochondrial DNA mutation–linked mitochondrial diseases and disorders caused by nuclear DNA mutations (Zhou et al., 1997; Rossignol et al., 2003; Haddad and Nakamura, 2015). Although several mechanisms of neuronal differential sensitivities in mitochondria-related disease have been proposed, our understanding is still incomplete (Dubinsky, 2009; Haddad and Nakamura, 2015). These unsolved problems could stem from multiple causes, including technical limitations and the complexity of Mitochondria are key contributors to the etiology of diseases associated with neuromuscular defects or neurodegeneration. How changes in cellular metabolism specifically impact neuronal intracellular processes and cause neuropathological events is still unclear. We here dissect the molecular mechanism by which mitochondrial dysfunction induced by Prel aberrant function mediates selective dendritic loss in Drosophila melanogaster class IV dendritic arborization neurons. Using in vivo ATP imaging, we found that neuronal cellular ATP levels during development are not correlated with the progression of dendritic loss. We searched for mitochondrial stress signaling pathways that induce dendritic loss and found that mitochondrial dysfunction is associated with increased eIF2α phosphorylation, which is sufficient to induce dendritic pathology in class IV arborization neurons. We also observed that eIF2α phosphorylation mediates dendritic loss when mitochondrial dysfunction results from other genetic perturbations. Furthermore, mitochondrial dysfunction induces translation repression in class IV neurons in an eIF2α phosphorylation-dependent manner, suggesting that differential translation attenuation among neuron subtypes is a determinant of preferential vulnerability. Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation