Han, Sinsuk;
Jeong, Yu Young;
Sheshadri, Preethi;
Cai, Qian;
(2020)
Mitophagy coordination with retrograde transport ensures the integrity of synaptic mitochondria.
Autophagy
, 16
(10)
pp. 1925-1927.
10.1080/15548627.2020.1810919.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Mitophagy coordination with retrograde transport ensures the integrity of synaptic mitochondria |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1080/15548627.2020.1810919 |
| Publisher version: | https://doi.org/10.1080/15548627.2020.1810919 |
| Language: | English |
| Additional information: | Alzheimer, mitophagosome, Nix, PRKN, RHEB, retrograde transport, SNAPIN, synaptic degeneration, synaptic mitochondrial deficits, synaptic mitophagy |
| Keywords: | Alzheimer, Cell Biology, Life Sciences & Biomedicine, mitophagosome, Nix, PRKN, retrograde transport, RHEB, Science & Technology, SNAPIN, synaptic degeneration, synaptic mitochondrial deficits, synaptic mitophagy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10173017 |
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