Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons.

Nuo Jia, Dhasarathan Ganesan, Hongyuan Guan, Yu Young Jeong, Sinsuk Han, Gavesh Rajapaksha, Marialaina Nissenbaum, Alexander W Kusnecov, Qian Cai
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Abstract

Hyperphosphorylation and aggregation of MAPT (microtubule-associated protein tau) is a pathogenic hallmark of tauopathies and a defining feature of Alzheimer disease (AD). Pathological MAPT/tau is targeted by macroautophagy/autophagy for clearance after being sequestered within autophagosomes, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic deficits have been shown to precede MAPT/tau pathology in tauopathy brains, it is unclear whether energy metabolism deficiency is involved in the pathogenesis of autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy neurons which, strikingly, leads to pronounced MAPT/tau clearance by boosting autophagy functionality through enhancements of mitochondrial biosynthesis and supply of phosphatidylethanolamine for autophagosome biogenesis. Furthermore, early anaplerotic stimulation of OXPHOS elevates autophagy activity and attenuates MAPT/tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of mitochondrial bioenergetic deficiency in tauopathy-related autophagy defects and suggests a new therapeutic strategy to prevent the buildup of pathological MAPT/tau in AD and other tauopathy diseases.Abbreviation: AA: antimycin A; AD, Alzheimer disease; ATP, adenosine triphosphate; AV, autophagosome/autophagic vacuole; AZ, active zone; Baf-A1: bafilomycin A1; CHX, cycloheximide; COX, cytochrome c oxidase; DIV, days in vitro; DRG, dorsal root ganglion; ETN, ethanolamine; FRET, Förster/fluorescence resonance energy transfer; FTD, frontotemporal dementia; Gln, glutamine; HA: hydroxylamine; HsMAPT/Tau, human MAPT; IMM, inner mitochondrial membrane; LAMP1, lysosomal-associated membrane protein 1; LIs, lysosomal inhibitors; MDAV, mitochondria-derived autophagic vacuole; MmMAPT/Tau, murine MAPT; NFT, neurofibrillary tangle; OCR, oxygen consumption rate; Omy: oligomycin; OXPHOS, oxidative phosphorylation; PPARGC1A/PGC-1alpha: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PE, phosphatidylethanolamine; phospho-MAPT/tau, hyperphosphorylated MAPT; PS, phosphatidylserine; PISD, phosphatidylserine decarboxylase;SQSTM1/p62, sequestosome 1; STX1, syntaxin 1; SYP, synaptophysin; Tg, transgenic; TCA, tricarboxylic acid; TEM, transmission electron microscopy.

线粒体生物能刺激自噬,以清除牛磺酸病神经元中的病理性 MAPT/Tau。
MAPT(微管相关蛋白 tau)的过度磷酸化和聚集是 tauopathies 的致病特征,也是阿尔茨海默病(AD)的决定性特征。病态的 MAPT/tau 被螯合在自噬体中后,会被大自噬/自噬作用清除,但自噬功能障碍在 tauopathy 中也有表现。虽然线粒体生物能不足已被证明先于tauopathy大脑中的MAPT/tau病理变化,但目前还不清楚能量代谢不足是否与自噬缺陷的发病机制有关。在这里,我们揭示了在tauopathy神经元中刺激无机代谢可恢复有缺陷的氧化磷酸化(OXPHOS),通过增强线粒体的生物合成和为自噬体生物生成提供磷脂酰乙醇胺来促进自噬功能,从而显著清除MAPT/tau。此外,早期无机刺激 OXPHOS 可提高自噬活性并减轻 MAPT/tau 病理变化,从而抵消 tauopathy 小鼠的记忆损伤。综上所述,我们的研究揭示了线粒体生物能不足在与tauopathy相关的自噬缺陷中的关键作用,并提出了一种新的治疗策略,以防止病理性MAPT/tau在AD和其他tauopathy疾病中的积累。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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