Mitochondrial import and degradation of amyloid-beta peptide

• Mitochondrial dysfunctions associated with amyloid-beta peptide (A beta) accumulation in mitochondria have been observed in Alzheimer's disease (AD) patients' brains and in AD mice models. A beta is produced by sequential action of beta- and gamma-secretases cleaving the amyloid precursor protein (APP). The gamma-secretase complex was found in mitochondria-associated endoplasmic reticulum membranes (MAM) suggesting that this could be a potential site of A beta production, from which A beta is further transported into the mitochondria. In vitro, A beta was shown to be imported into the mitochondria through the translocase of the outer membrane (TOM) complex. The mitochondrial presequence protease (Prep) is responsible for A beta degradation reducing toxic effects of A beta on mitochondrial functions. The proteolytic activity of PreP is, however, lower in AD brain temporal lobe mitochondria and in AD transgenic mice models, possibly due to an increased reactive oxygen species (ROS) production. Here, we review the intracellular mechanisms of A beta production, its mitochondrial import and the intra-mitochondrial degradation. We also discuss the implications of a reduced efficiency of mitochondrial A beta clearance for AD. Understanding the underlying mechanisms may provide new insights into mitochondria related pathogenesis of AD and development of drug therapy against AD. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biofysik (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biophysics (hsv//eng)

Keyword

Mitochondria

Amyloid-beta peptide

MAM

Degradation

Presequence protease

PreP

Publication and Content Type

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