Parkin mitochondria in the autophagosome

University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
The Journal of Cell Biology (Impact Factor: 9.83). 01/2009; 183(5):757-9. DOI: 10.1083/jcb.200810184
Source: PubMed


Narendra et al. (see p. 795 of this issue) have made an exciting new discovery that links the fields of mitochondrial quality control and the genetics of Parkinson's disease (PD). Through an elegant series of high-resolution imaging experiments, they are the first to provide evidence that the PARK2 gene product Parkin is selectively recruited to damaged or uncoupled mitochondria. This recruitment leads to the clearance of the organelles through the autophagosome, demonstrating a primary function for Parkin in the regulation of mitochondrial turnover. This work significantly increases our understanding of PD and provides a new framework for the development of therapeutic interventions.

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Available from: Heidi M Mcbride, Dec 12, 2013
    • "ubiquitinated proteins and promotes the formation of autophagosomes that engulf damaged organelles, including mitochondria (McBride, 2008; Mizushima et al., 2011). A block in autophagy has been shown to correlate with an upregulation of p62 because cells treated with 3-MA, a compound that blocks the initiation of autophagy, as well as ATG5 À/À and ATG7 À/À knockout mouse cells that show reduced autophagy, both show increased levels of p62 (Klionsky et al., 2012; Komatsu et al., 2007; Tanabe et al., 2011). "
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    ABSTRACT: The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.
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    • "Indeed, parkin prevents neuronal apoptosis through inhibition of the JNK signaling pathway in a manner dependent on its E3 ligase activity [105]. The neuroprotective function of parkin has also been suggested to result from its selective recruitment to damaged mitochondria, where it promotes the autophagic removal of the ROS-generating organelles [106] [107]. "
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    ABSTRACT: The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.
    Preview · Article · Apr 2010 · Biochimica et Biophysica Acta
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    • "The mitochondrial pathology in PINK1-deficient animals might be caused by an insufficient recruitment of Parkin followed by an impairment of mitochondrial turnover (Ref. 43). However, given that Parkin is capable of rescuing mitochondrial dysfunction caused by the loss of PINK1, it is unclear whether a direct molecular interaction between PINK1 and Parkin is essential for efficient removal of damaged mitochondria. "
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    ABSTRACT: The human brain is a highly complex organ with remarkable energy demands. Although it represents only 2% of the total body weight, it accounts for 20% of all oxygen consumption, reflecting its high rate of metabolic activity. Mitochondria have a crucial role in the supply of energy to the brain. Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders. Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components. Here, we review some of the most recent advances in the understanding of mitochondrial stress-control pathways, with a particular focus on how defects in such pathways might contribute to neurodegenerative disease.
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