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Abstract Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation. 

Abstract Potato virus Y(PVY,Potyviridae) is among the most important viral pathogens of potato. The potato resistance geneNy_tbrconfers hypersensitive resistance to the ordinary strain of PVY (PVY^O), but not the necrotic strain (PVY^N). Here, we unveil that residue 247 of PVY helper component proteinase (HCPro) acts as a central player controllingNy_tbrstrain‐specific activation. We found that substituting the serine at 247 in the HCPro of PVY^O(HCPro^O) with an alanine as in PVY^NHCPro (HCPro^N) disruptsNy_tbrrecognition. Conversely, an HCPro^Nmutant carrying a serine at position 247 triggers defence. Moreover, we demonstrate that plant defences are induced against HCPro^Omutants with a phosphomimetic or another phosphorylatable residue at 247, but not with a phosphoablative residue, suggesting that phosphorylation could modulateNy_tbrresistance. Extending beyond PVY, we establish that the same response elicited by the PVY^OHCPro is also induced by HCPro proteins from other members of thePotyviridaefamily that have a serine at position 247, but not by those with an alanine. Together, our results provide further insights in the strain‐specific PVY resistance in potato and infer a broad‐spectrum detection mechanism of plant potyvirus effectors contingent on a single amino acid residue.