Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients

Xinglong Wang, Bo Su, Hisashi Fujioka, Xiongwei Zhu

Research output: Contribution to journalArticlepeer-review

266 Scopus citations

Abstract

Mitochondrial function relies heavily on its morphology and distribution, alterations of which have been increasingly implicated in neurodegenerative diseases, such as Alzheimer's disease (AD). In this study, we found abnormal mitochondrial distribution characterized by elongated mitochondria that accumulated in perinuclear areas in 19.3% of sporadic AD (sAD) fibroblasts, which was in marked contrast to their normally even cytoplasmic distribution in the majority of human fibroblasts from normal subjects (>95%). Interestingly, levels of dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution, were decreased significantly in sAD fibroblasts. To explore the potential role of DLP1 in mediating mitochondrial abnormalities in sAD fibroblasts, both the overexpression of a dominant negative DLP1 mutant and the reduced expression of DLP1 by miR RNAi in human fibroblasts from normal subjects significantly increased mitochondrial abnormalities. Moreover, overexpression of wild-type DLP1 in sAD fibroblasts rescued these mitochondrial abnormalities. Based on these data, we conclude that DLP1 reduction causes mitochondrial abnormalities in sAD fibroblasts. We further demonstrate that elevated oxidative stress and increased amyloid β production are likely the potential pathogenic factors that cause DLP1 reduction and abnormal mitochondrial distribution in AD cells.

Original languageEnglish (US)
Pages (from-to)470-482
Number of pages13
JournalAmerican Journal of Pathology
Volume173
Issue number2
DOIs
StatePublished - Aug 2008
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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