CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease

J. Byun, S. M. Son, M. Y. Cha, M. Shong, Y. J. Hwang, Y. Kim, H. Ryu, M. Moon, K. S. Kim, I. Mook-Jung

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mitochondrial dysfunction, often characterized by massive fission and other morphological abnormalities, is a well-known risk factor for Alzheimer's disease (AD). One causative mechanism underlying AD-associated mitochondrial dysfunction is thought to be amyloid-β (Aβ), yet the pathways between Aβ and mitochondrial dysfunction remain elusive. In this study, we report that CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Aβ-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed Aβ undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with Aβ. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in Aβ-treated cells. Conversely, Crif1 overexpression prevented Aβ-induced mitochondrial dysfunction and cell death. Finally, we show that Aβ-induced downregulation of Crif1 is mediated by enhanced reactive oxygen species (ROS) and ROS-dependent sumoylation of the transcription factor specificity protein 1 (Sp1). These results identify the ROS-Sp1-Crif1 pathway to be a new mechanism underlying Aβ-induced mitochondrial dysfunction and suggest that ROS-mediated downregulation of Crif1 is a crucial event in AD pathology. We propose that Crif1 may serve as a novel therapeutic target in the treatment of AD.

Original languageEnglish
Pages (from-to)959-973
Number of pages15
JournalCell Death and Differentiation
Volume22
Issue number6
DOIs
Publication statusPublished - 2015 Jun 1

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Alzheimer Disease
Reactive Oxygen Species
Down-Regulation
Sp1 Transcription Factor
Sumoylation
Species Specificity
Brain
RNA Interference
Amyloid
Membrane Proteins
Cell Death
Pathology
Phenotype
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Byun, J. ; Son, S. M. ; Cha, M. Y. ; Shong, M. ; Hwang, Y. J. ; Kim, Y. ; Ryu, H. ; Moon, M. ; Kim, K. S. ; Mook-Jung, I. / CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 6. pp. 959-973.
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CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease. / Byun, J.; Son, S. M.; Cha, M. Y.; Shong, M.; Hwang, Y. J.; Kim, Y.; Ryu, H.; Moon, M.; Kim, K. S.; Mook-Jung, I.

In: Cell Death and Differentiation, Vol. 22, No. 6, 01.06.2015, p. 959-973.

Research output: Contribution to journalArticle

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AU - Son, S. M.

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AU - Kim, Y.

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