TY - JOUR
T1 - Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons
AU - Cai, Qian
AU - Zakaria, Hesham Mostafa
AU - Simone, Anthony
AU - Sheng, Zu Hang
N1 - Funding Information:
We thank R.J. Youle for helpful discussions; R.J. Youle, B. Lu, and M.J. LaVoie for Parkin DNA constructs; the members of the Sheng laboratory for technical assistance and helpful discussions; and S. Yang and D. Schoenberg for editing. This work was supported by the Intramural Research Program of NINDS, NIH (Z-H.S.), the NIH Pathway to Independence Award K99 (Q.C.), and Howard Hughes Medical Institute-NIH Research Scholars Program (H.M.Z.)
PY - 2012/3/20
Y1 - 2012/3/20
N2 - Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function [1-8]. Translocation of Parkin to damaged mitochondria induces mitophagy in many nonneuronal cell types [9-16]. However, evidence showing Parkin translocation in primary neurons is controversial [9, 15, 17, 18], leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Δψ m-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with nonneuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondrial transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring-like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport.
AB - Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function [1-8]. Translocation of Parkin to damaged mitochondria induces mitophagy in many nonneuronal cell types [9-16]. However, evidence showing Parkin translocation in primary neurons is controversial [9, 15, 17, 18], leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Δψ m-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with nonneuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondrial transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring-like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport.
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U2 - 10.1016/j.cub.2012.02.005
DO - 10.1016/j.cub.2012.02.005
M3 - Article
C2 - 22342752
AN - SCOPUS:84858701257
SN - 0960-9822
VL - 22
SP - 545
EP - 552
JO - Current Biology
JF - Current Biology
IS - 6
ER -