Loss of HIPK2 Protects Neurons from Mitochondrial Toxins by Regulating Parkin Protein Turnover.

Autor:	Zhang J; Department of Pathology, University of California, San Francisco, San Francisco, California 94143.; Pathology Service 113B, VA Medical Center, San Francisco, California 94121., Shang Y; Department of Pathology, University of California, San Francisco, San Francisco, California 94143., Kamiya S; Department of Pathology, University of California, San Francisco, San Francisco, California 94143., Kotowski SJ; Department of Neurology, University of California, San Francisco, San Francisco, California 94122, and.; Gladstone Institute of Neurological Disease, San Francisco, California 94158., Nakamura K; Department of Neurology, University of California, San Francisco, San Francisco, California 94122, and.; Gladstone Institute of Neurological Disease, San Francisco, California 94158., Huang EJ; Department of Pathology, University of California, San Francisco, San Francisco, California 94143, eric.huang2@ucsf.edu.; Pathology Service 113B, VA Medical Center, San Francisco, California 94121.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2020 Jan 15; Vol. 40 (3), pp. 557-568. Date of Electronic Publication: 2019 Nov 27.
DOI:	10.1523/JNEUROSCI.2017-19.2019
Abstrakt:	Mitochondria are important sources of energy, but they are also the target of cellular stress, toxin exposure, and aging-related injury. Persistent accumulation of damaged mitochondria has been implicated in many neurodegenerative diseases. One highly conserved mechanism to clear damaged mitochondria involves the E3 ubiquitin ligase Parkin and PTEN-induced kinase 1 (PINK1), which cooperatively initiate the process called mitophagy that identifies and eliminates damaged mitochondria through the autophagosome and lysosome pathways. Parkin is a mostly cytosolic protein, but is rapidly recruited to damaged mitochondria and target them for mitophagy. Moreover, Parkin interactomes also involve signaling pathways and transcriptional machinery critical for survival and cell death. However, the mechanism that regulates Parkin protein level remains poorly understood. Here, we show that the loss of homeodomain interacting protein kinase 2 (HIPK2) in neurons and mouse embryonic fibroblasts (MEFs) has a broad protective effect from cell death induced by mitochondrial toxins. The mechanism by which Hipk2 -/- neurons and MEFs are more resistant to mitochondrial toxins is in part due to the role of HIPK2 and its kinase activity in promoting Parkin degradation via the proteasome-mediated mechanism. The loss of HIPK2 leads to higher cytosolic Parkin protein levels at basal conditions and upon exposure to mitochondrial toxins, which protects mitochondria from toxin-induced damage. In addition, Hipk2 -/- neurons and MEFs show increased expression of PGC-1α (peroxisome proliferator-activated receptor-γ coactivator 1), a Parkin downstream target that can provide additional benefits via transcriptional activation of mitochondrial genes. Together, these results reveal a previously unrecognized avenue to target HIPK2 in neuroprotection via the Parkin-mediated pathway. SIGNIFICANCE STATEMENT In this study, we provide evidence that homeodomain interacting protein kinase 2 (HIPK2) and its kinase activity promote Parkin degradation via the proteasome-mediated pathway. The loss of HIPK2 increases cytosolic and mitochondrial Parkin protein levels under basal conditions and upon exposure to mitochondrial toxins, which protect mitochondria from toxin-induced damage. In addition, Hipk2 -/- neurons and mouse embryonic fibroblasts also show increased expression of PGC-1α (peroxisome proliferator-activated receptor-γ coactivator 1), a Parkin downstream target that can provide additional benefits via transcriptional activation of mitochondrial genes. These results indicate that targeting HIPK2 and its kinase activity can have neuroprotective effects by elevating Parkin protein levels. (Copyright © 2020 the authors.)
Databáze:	MEDLINE
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