Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy.
Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these "mito-aggresome" structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP-causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.
Lee
Joo-Yong
JY
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Nagano
Yoshito
Y
Taylor
J Paul
JP
Lim
Kah Leong
KL
Yao
Tso-Pang
TP
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002478:Cells, Cultured; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
J Biol Chem. 2005 Dec 2;280(48):40282-92
16192271
J Biol Chem. 2004 Jul 16;279(29):30265-73
15123692
Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13354-9
11078524
J Neurosci. 2005 Feb 23;25(8):2002-9
15728840
Autophagy. 2007 Nov-Dec;3(6):643-5
17912024
Eur J Neurosci. 2002 Dec;16(11):2136-48
12473081
Nature. 2008 Feb 28;451(7182):1069-75
18305538
Cell Motil Cytoskeleton. 2002 Sep;53(1):26-38
12211113
Nat Med. 2001 Oct;7(10):1144-50
11590439
J Cell Biol. 2002 Aug 19;158(4):647-57
12186850
Nature. 2002 May 23;417(6887):455-8
12024216
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):378-83
19966284
EMBO J. 2010 Mar 3;29(5):969-80
20075865
Nat Genet. 2000 Jul;25(3):302-5
10888878
J Neurochem. 2005 Apr;93(2):422-31
15816865
Nat Rev Neurosci. 2006 Mar;7(3):207-19
16495942
Hum Mol Genet. 2005 Sep 1;14(17):2571-86
16049031
Cell. 2003 Dec 12;115(6):727-38
14675537
J Cell Biol. 2008 Dec 1;183(5):795-803
19029340
N Engl J Med. 2000 May 25;342(21):1560-7
10824074
J Cell Biol. 2007 Sep 10;178(6):1025-38
17846173
J Biol Chem. 2007 Aug 17;282(33):24131-45
17580304