The role of mitochondrial deficits in tauopathy-linked autophagy defects

PROJECT SUMMARY Alzheimer’s disease (AD) is pathologically characterized by the presence of extracellular amyloid plaques consisting of amyloid b (Ab) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau) in afflicted brains. In AD, tau pathology correlates with neuronal death and cognitive dysfunction better than amyloid plaques. Thus, a deeper understanding of the pathogenic mechanisms of tau is needed. Autophagy is a key cellular quality-control mechanism in neurons and pathological tau is known to be degraded within lysosomes after being targeted by autophagy. Autophagy perturbation has been indicated in tauopathy patient brains and cellular models, but the underlying mechanism remains largely unexplored. Mitochondrial abnormalities are a prominent feature of tauopathy. We recently revealed that deficits in synaptic distribution of mitochondria occur early in tauopathy preceding tau pathology, which is caused by reduced expression of Mitochondrial Rho GTPase (Miro), a well-studied KIF5 motor receptor driving mitochondrial anterograde transport. In a pilot study investigating whether such early mitochondrial deficits contribute to autophagy deficits and tau buildup in cultured tauopathy neurons, we have observed that overexpression of Miro increases autophagosome/autophagic vacuole (AV) biogenesis which leads to a significant reduction in p-tau accumulation. Recent studies have uncovered that phosphatidylethanolamine (PE), a major component of the AV membrane, plays a pivotal role in autophagy initiation and AV membrane elongation, and that the supply of PE constitutes a limiting factor for autophagy activity. In mammalian cells, PE is mainly synthesized in the endoplasmic reticulum (ER) and mitochondria. Prior work implies that pools of PE from these two distinct biosynthetic pathways are compartmentalized and do not mix freely within cells. Importantly, we found that tauopathy neurons exhibited mitochondrial PE biosynthesis impairment whereas overexpression of Miro led to an increase in mitochondrial supply of PE for AV biogenesis which was abolished by inhibition of PE biosynthesis in mitochondria but not in the ER, thus supporting a novel role of Miro in mitochondrial PE biosynthesis essential for AV biogenesis and tau clearance in tauopathy neurons. However, detailed mechanisms underlying this new role of Miro have yet to be identified. Based on these preliminary studies, we hypothesized that Miro overexpression rescues autophagy deficits and alleviates tau pathology by enhancing the PE biosynthetic pathway in mitochondria, thereby mitigating memory deficits in tauopathy. We will determine the mechanism underlying Miro-enhanced autophagy in tauopathy neurons and examine whether neuronal overexpression of Miro rescues autophagy deficits and ameliorates tau pathology/cognitive deficits in tauopathy mice. The successful completion of this study will provide mechanistic insights into a novel role of Miro in mitochondrial PE biosynthesis for autophagy-mediated tau clearance and will likely establish Miro-enhanced autophagy as a new, potentially therapeutic strategy for combating tauopathies.