Jia Nuo, Ganesan Dhasarathan, Guan Hongyuan, Jeong Yu Young, Han Sinsuk, Rajapaksha Gavesh, Nissenbaum Marialaina, Kusnecov Alexander W, Cai Qian
Department of Cell Biology, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Department of Psychology, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Autophagy. 2025 Jan;21(1):54-79. doi: 10.1080/15548627.2024.2392408. Epub 2024 Sep 3.
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.: AA: antimycin A; AD, Alzheimer disease; ATP, adenosine triphosphate; AV, autophagosome/autophagic vacuole; AZ, active zone; Baf-A1: bafilomycin A; CHX, cycloheximide; COX, cytochrome c oxidase; DIV, days ; 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.
微管相关蛋白tau（MAPT）的过度磷酸化和聚集是tau蛋白病的致病标志，也是阿尔茨海默病（AD）的一个决定性特征。病理性MAPT/tau在被隔离于自噬体后会被巨自噬/自噬靶向清除，但tau蛋白病中存在自噬功能障碍。虽然线粒体生物能量缺陷已被证实在tau蛋白病大脑中先于MAPT/tau病理出现，但尚不清楚能量代谢缺陷是否参与自噬缺陷的发病机制。在这里，我们发现刺激回补性代谢可恢复tau蛋白病神经元中缺陷的氧化磷酸化（OXPHOS），令人惊讶的是，这通过增强线粒体生物合成和为自噬体生物发生提供磷脂酰乙醇胺来提高自噬功能，从而导致显著的MAPT/tau清除。此外，早期对OXPHOS的回补性刺激可提高自噬活性并减轻MAPT/tau病理，从而抵消tau蛋白病小鼠的记忆损伤。综上所述，我们的研究揭示了线粒体生物能量缺陷在tau蛋白病相关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AD和其他tau蛋白病中病理性MAPT/tau的积累。：AA：抗霉素A；AD，阿尔茨海默病；ATP，三磷酸腺苷；AV，自噬体/自噬泡；AZ，活性区；Baf-A1：巴弗洛霉素A；CHX，放线菌酮；COX，细胞色素c氧化酶；DIV，天数；DRG，背根神经节；ETN，乙醇胺；FRET，福斯特/荧光共振能量转移；FTD，额颞叶痴呆；Gln，谷氨酰胺；HA：羟胺；HsMAPT/Tau，人MAPT；IMM，线粒体内膜；LAMP1，溶酶体相关膜蛋白1；LIs，溶酶体抑制剂；MADV，线粒体衍生的自噬泡；MmMAPT/Tau，鼠MAPT；NFT，神经原纤维缠结；OCR，耗氧率；Omy：寡霉素；OXPHOS，氧化磷酸化；PPARGC1A/PGC-1α：过氧化物酶体增殖物激活受体γ共激活因子1α；PE，磷脂酰乙醇胺；磷酸化MAPT/tau，过度磷酸化的MAPT；PS，磷脂酰丝氨酸；PISD，磷脂酰丝氨酸脱羧酶；SQSTM1/p62，隔离体1；STX1， syntaxin 1；SYP，突触素；Tg，转基因；TCA，三羧酸循环；TEM，透射电子显微镜。
