Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer's disease-like calcium dysregulation

Gary E Gibson; Huan-Lian Chen; Hui Xu; Linghua Qiu; Zuoshang Xu; Travis T Denton; Qingli Shi

doi:10.1016/j.neurobiolaging.2011.11.003

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Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer's disease-like calcium dysregulation

Journal article

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Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer's disease-like calcium dysregulation

Gary E Gibson, Huan-Lian Chen, Hui Xu, Linghua Qiu, Zuoshang Xu, Travis T Denton and Qingli Shi

Neurobiology of aging, Vol.33(6), pp.1121.e13-1121.e24

06/2012

DOI: https://doi.org/10.1016/j.neurobiolaging.2011.11.003

Handle:

https://hdl.handle.net/2376/100493

PMCID: PMC3321099

PMID: 22169199

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https://doi.org/10.1016/j.neurobiolaging.2011.11.003View

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Abstract

Mitochondria - enzymology

Alzheimer Disease - physiopathology

Mice, Inbred C57BL

Mitochondrial Proteins - antagonists & inhibitors

Cells, Cultured

Mice, Transgenic

Mitochondrial Proteins - genetics

Alzheimer Disease - enzymology

Ketoglutarate Dehydrogenase Complex - genetics

Ketoglutarate Dehydrogenase Complex - antagonists & inhibitors

Ketoglutarate Dehydrogenase Complex - deficiency

Animals

Calcium - physiology

Cell Line, Tumor

Mice

Mitochondrial Proteins - deficiency

Understanding the molecular sequence of events that culminate in multiple abnormalities in brains from patients that died with Alzheimer's disease (AD) will help to reveal the mechanisms of the disease and identify upstream events as therapeutic targets. The activity of the mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC) in homogenates from autopsy brain declines with AD. Experimental reductions in KGDHC in mouse models of AD promote plaque and tangle formation, the hallmark pathologies of AD. We hypothesize that deficits in KGDHC also lead to the abnormalities in endoplasmic reticulum (ER) calcium stores and cytosolic calcium following K(+) depolarization that occurs in cells from AD patients and transgenic models of AD. The activity of the mitochondrial enzyme KGDHC was diminished acutely (minutes), long-term (days), or chronically (weeks). Acute inhibition of KGDHC produced effects on calcium opposite to those in AD, while the chronic or long-term inhibition of KGDHC mimicked the AD-related changes in calcium. Divergent changes in proteins released from the mitochondria that affect endoplasmic reticulum calcium channels may underlie the selective cellular consequences of acute versus longer term inhibition of KGDHC. The results suggest that the mitochondrial abnormalities in AD can be upstream of those in calcium.

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Title: Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer's disease-like calcium dysregulation
Creators: Gary E Gibson - Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA. ggibson@med.cornell.edu
Huan-Lian Chen
Hui Xu
Linghua Qiu
Zuoshang Xu
Travis T Denton
Qingli Shi
Publication Details: Neurobiology of aging, Vol.33(6), pp.1121.e13-1121.e24
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: P01 AG014930-12 / NIA NIH HHS P01 AG014930 / NIA NIH HHS AG14930 / NIA NIH HHS
Identifiers: 99900546540401842
Language: English
Resource Type: Journal article