Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

By Derek P. Narendra, Atsushi Tanaka, D. Suen, R. Youle. Journal of Cell Biology, 2008

4,017 citations recorded by the source corpus.

Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/4ab7a998becb79fbca5307a338b7e6e34805ca58

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Citations in the corpus

A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. (2012, positive): “In addition to cargo selectivity, we further distinguished MDVs from mitochondrial fragments undergoing mitophagy by infecting the cells with dominant-negative DRP1, which blocks mitophagy [8, 9].”
During autophagy mitochondria elongate, are spared from degradation and sustain cell viability (2011, neutral): “and targets dysfunctional organelles to the autophagosom”
Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin (2010, background): “Important insight into the mechanism by which Parkin regulates mitochondrial homeostasis has revealed that upon mitochondrial depolarization Parkin translocates from the cytoplasm to accumulate on a subset of mitochondria and promotes their degradation by autophagy (18).”
The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “Parkin was shown to translocate selectively to energetically impaired mitochondria that were destined to autophagy independent of ROS production and morphology (75, 114).”
Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons (2012, background): “In contrast, mitochondria have been shown to be specifically targeted for degradation by autophagy in response to stress or insult (Narendra et al., 2008).”
Mitochondria and cell death: outer membrane permeabilization and beyond (2010, background): “Mitophagy triggers include the loss of mitochondrial membrane potential and membrane permeability transitio”
Mitochondrial Dynamics in the Regulation of Nutrient Utilization and Energy Expenditure (2013, background): “The U3-ubiquitin ligase Parkin (mutated in Parkinson’s disease), through PINK1 serine-threonine kinase activity, is recruited to depolarized mitochondria to target them for mitophagy (Narendra et al., 2008; Vives-Bauza et al., 2010; Ziviani et al., 2010).”
Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. (2013, background): “Parkin is an E3 ubiquitin ligase that ubiquitinates mitochondrial outer membrane target proteins (Narendra et al. 2008, 2009, 2010; Guo 2010; Youle and van der Bliek 2012).”
Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL (2010, methodology): “Upon mitochondrial damage or uncoupling, Parkin relocalizes to mitochondria and can mediate the autophagic elimination of damaged mitochondria (Narendra et al., 2008), which is dependent on PINK1 kinase activity (Geisler et al., 2010; Matsuda et al., 2010; Narendra et al., 2010; Vives-Bauza et al.,…”
Deubiquitylating enzymes and drug discovery: emerging opportunities (2017, background): “However, in response to stresses such as membrane depolarization, Parkin is recruited to mitochondria to promote mitophagy 145 .”
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 (2010, neutral): “dtd" [ ]> Parkinson's disease is the most common movement disorder and results from selective and massive loss of dopamine-containing neurons in the Substantia Nigra pars compacta (SNpc”