Mitophagy coordination with retrograde transport ensures the integrity of synaptic mitochondria
| Autor: | Sinsuk Han, Yu Young Jeong, Preethi Sheshadri, Qian Cai |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Dynein Mitochondrion Small hairpin RNA 03 medical and health sciences Mice Alzheimer Disease Mitophagy Autophagy Animals Molecular Biology Late endosome Amyloid beta-Peptides 030102 biochemistry & molecular biology biology Cell Biology Articles Cell biology Mitochondria 030104 developmental biology Synapses Axoplasmic transport biology.protein RHEB |
| Zdroj: | EMBO Rep |
| ISSN: | 1554-8635 |
| Popis: | Mitochondria sustain various essential functions at synaptic terminals. Synaptic mitochondria deficits have been implicated in early Alzheimer disease (AD) pathophysiology. Mitophagy, a selective autophagy for removal of damaged mitochondria, plays a key role in mitochondrial quality control in neurons. However, fundamental questions remain unanswered as to whether mitophagy regulates synaptic mitochondrial integrity and whether AD-associated early deficits in synaptic mitochondria are attributed to mitophagy failure. We have recently revealed that the integrity of synaptic mitochondria is maintained by a coordination of RHEB-mediated mitophagy with dynein- and SNAPIN-driven retrograde transport. We demonstrate that increased mitophagy initiation, coupled with defective retrograde transport, triggers mitophagy stress at AD synapses. Excitingly, SNAPIN-enhanced retrograde transport reduces synaptic mitophagy stress and ameliorates mitochondrial deficits, thereby counteracting synaptic damage in AD mouse brains. Therefore, our study provides new mechanistic insights into how mitophagy facilitates synaptic mitochondrial maintenance and how mitophagy failure exacerbates AD-linked mitochondrial defects and synaptic degeneration. Abbreviation: AD: Alzheimer disease; Aβ: amyloid-β; APP: amyloid beta precursor protein; CCCP: carbonyl cyanide m-chlorophenylhydrazone; LE: late endosome; Δψm, mitochondrial membrane potential; RHEB: Ras homolog enriched in brain; RNAi: RNA interference; shRNA: small hairpin RNA; Tg: transgenic. |
| Databáze: | OpenAIRE |
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