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A Novel Non-Apoptotic Role of Procaspase-3 in the Regulation of Mitochondrial Biogenesis Activators

Title
A Novel Non-Apoptotic Role of Procaspase-3 in the Regulation of Mitochondrial Biogenesis Activators
Authors
Kim J.-S.Ha J.-Y.Yang S.-J.Son J.H.
Ewha Authors
손형진
SCOPUS Author ID
손형진scopus
Issue Date
2018
Journal Title
Journal of Cellular Biochemistry
ISSN
0730-2312JCR Link
Citation
vol. 119, no. 1, pp. 347 - 357
Keywords
APOPTOSISCASPASE-3MITOCHONDRIAL BIOGENESIS ACTIVATORMITOCHONDRIAL DYSFUNCTIONPARKINSON'S DISEASETfam
Publisher
Wiley-Liss Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The executioner caspase-3 has been proposed as a pharmacological intervention target to preserve degenerating dopaminergic (DA) neurons because apoptotic mechanisms involving caspase-3 contribute, at least in part, to the loss of DA neurons in patients and experimental models of Parkinson's disease (PD). Here, we determined that genetic intervention of caspase-3 was sufficient to prevent cell death against oxidative stress (OS), accompanied by unexpected severe mitochondrial dysfunction. Specifically, as we expected, caspase-3-deficient DA neuronal cells were very significantly resistant to OS-induced cell death, while the activation of the initiator caspase-9 by OS was preserved. Moreover, detailed phenotypic characterization of caspase-3-deficient DA cells revealed severe mitochondrial dysfunction, including an accumulation of damaged mitochondria with a characteristic swollen structure and broken cristae, reduced membrane potential, increased levels of reactive oxygen species (ROS), and deficits in mitochondrial oxidative phosphorylation (OXPHOS) enzymes. Of great interest, we found that mitochondrial biogenesis was dramatically decreased in caspase-3-deficient DA cells, whereas their capability of mitophagy was normal. In accordance with this observation, caspase-3 gene knock down (KD) resulted in dramatically decreased expression of the key transcriptional activators of mitochondrial biogenesis, such as Tfam and Nrf-1, implicating a non-apoptotic role of procaspase-3 in mitochondrial biogenesis. Therefore, a prolonged anti-apoptotic intervention targeting caspase-3 should be considered with caution due to the potential adverse effects in mitochondria dynamics resulting from a novel potential functional role of procaspase-3 in mitochondrial biogenesis via regulating the expression of mitochondrial biogenesis activators. J. Cell. Biochem. 119: 347–357, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
DOI
10.1002/jcb.26186
Appears in Collections:
약학대학 > 약학과 > Journal papers
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