Limits...
Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells.

Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG - J. Cell Biol. (2003)

Bottom Line: Mutational studies show that the acidic domain, which spans sequence 220-290 of APP, causes the transmembrane arrest with the COOH-terminal 73-kD portion of the protein facing the cytoplasmic side.Accumulation of full-length APP in the mitochondrial compartment in a transmembrane-arrested form, but not lacking the acidic domain, caused mitochondrial dysfunction and impaired energy metabolism.These results show, for the first time, that APP is targeted to neuronal mitochondria under some physiological and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Alzheimer's amyloid precursor protein 695 (APP) is a plasma membrane protein, which is known to be the source of the toxic amyloid beta (Abeta) peptide associated with the pathogenesis of Alzheimer's disease (AD). Here we demonstrate that by virtue of its chimeric NH2-terminal signal, APP is also targeted to mitochondria of cortical neuronal cells and select regions of the brain of a transgenic mouse model for AD. The positively charged residues at 40, 44, and 51 of APP are critical components of the mitochondrial-targeting signal. Chemical cross-linking together with immunoelectron microscopy show that the mitochondrial APP exists in NH2-terminal inside transmembrane orientation and in contact with mitochondrial translocase proteins. Mutational studies show that the acidic domain, which spans sequence 220-290 of APP, causes the transmembrane arrest with the COOH-terminal 73-kD portion of the protein facing the cytoplasmic side. Accumulation of full-length APP in the mitochondrial compartment in a transmembrane-arrested form, but not lacking the acidic domain, caused mitochondrial dysfunction and impaired energy metabolism. These results show, for the first time, that APP is targeted to neuronal mitochondria under some physiological and pathological conditions.

Show MeSH

Related in: MedlinePlus

A proposed model for the mitochondrial targeting and accumulation of transmembrane- arrested APP affecting mitochondrial functions.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172865&req=5

fig8: A proposed model for the mitochondrial targeting and accumulation of transmembrane- arrested APP affecting mitochondrial functions.

Mentions: In support of previous studies (Hatanpaa et al., 1998; Webster et al., 1998), our results show that increased production of extracellular Aβ peptide in cells overexpressing the 3M/APP and Δ220–290/APP mutant proteins did not cause changes in mitochondrial function or ATP synthesis. The accumulation of Aβ in the Golgi network might be directly related to reduced APP trafficking to the PM and decreased Aβ secretion in cells transfected with WT/APP. These results are in agreement with the view that accumulation of COOH-terminal fragments in the intracellular compartments impairs Aβ secretion and APP trafficking (Greenfield et al., 1999; Maltese et al., 2001). However, expression of 3M/APP and Δ220–290/APP mutant proteins that failed to cause mitochondrial dysfunction showed no accumulation of Aβ peptides in the Golgi network, suggesting that mitochondrial function may somehow be associated with the accumulation of toxic Aβ peptides in the secretory pathway. Although the precise relationship between mitochondrial injury and altered trafficking of cargo through the Golgi network remains unknown, our results are in line with a previous study implicating the role of mitochondrial function in the accumulation of COOH-terminal fragments of APP in the secretory pathway (Busciglio et al., 2002). Based on these, we propose a model (Fig. 8) for the bimodal targeting of APP through its NH2-terminal chimeric signal. We further propose that under increased APP expression, a progressive accumulation of transmembrane-arrested APP causes perturbation of mitochondrial function, which in turn results in impairment of energy metabolism.


Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells.

Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG - J. Cell Biol. (2003)

A proposed model for the mitochondrial targeting and accumulation of transmembrane- arrested APP affecting mitochondrial functions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172865&req=5

fig8: A proposed model for the mitochondrial targeting and accumulation of transmembrane- arrested APP affecting mitochondrial functions.
Mentions: In support of previous studies (Hatanpaa et al., 1998; Webster et al., 1998), our results show that increased production of extracellular Aβ peptide in cells overexpressing the 3M/APP and Δ220–290/APP mutant proteins did not cause changes in mitochondrial function or ATP synthesis. The accumulation of Aβ in the Golgi network might be directly related to reduced APP trafficking to the PM and decreased Aβ secretion in cells transfected with WT/APP. These results are in agreement with the view that accumulation of COOH-terminal fragments in the intracellular compartments impairs Aβ secretion and APP trafficking (Greenfield et al., 1999; Maltese et al., 2001). However, expression of 3M/APP and Δ220–290/APP mutant proteins that failed to cause mitochondrial dysfunction showed no accumulation of Aβ peptides in the Golgi network, suggesting that mitochondrial function may somehow be associated with the accumulation of toxic Aβ peptides in the secretory pathway. Although the precise relationship between mitochondrial injury and altered trafficking of cargo through the Golgi network remains unknown, our results are in line with a previous study implicating the role of mitochondrial function in the accumulation of COOH-terminal fragments of APP in the secretory pathway (Busciglio et al., 2002). Based on these, we propose a model (Fig. 8) for the bimodal targeting of APP through its NH2-terminal chimeric signal. We further propose that under increased APP expression, a progressive accumulation of transmembrane-arrested APP causes perturbation of mitochondrial function, which in turn results in impairment of energy metabolism.

Bottom Line: Mutational studies show that the acidic domain, which spans sequence 220-290 of APP, causes the transmembrane arrest with the COOH-terminal 73-kD portion of the protein facing the cytoplasmic side.Accumulation of full-length APP in the mitochondrial compartment in a transmembrane-arrested form, but not lacking the acidic domain, caused mitochondrial dysfunction and impaired energy metabolism.These results show, for the first time, that APP is targeted to neuronal mitochondria under some physiological and pathological conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

ABSTRACT
Alzheimer's amyloid precursor protein 695 (APP) is a plasma membrane protein, which is known to be the source of the toxic amyloid beta (Abeta) peptide associated with the pathogenesis of Alzheimer's disease (AD). Here we demonstrate that by virtue of its chimeric NH2-terminal signal, APP is also targeted to mitochondria of cortical neuronal cells and select regions of the brain of a transgenic mouse model for AD. The positively charged residues at 40, 44, and 51 of APP are critical components of the mitochondrial-targeting signal. Chemical cross-linking together with immunoelectron microscopy show that the mitochondrial APP exists in NH2-terminal inside transmembrane orientation and in contact with mitochondrial translocase proteins. Mutational studies show that the acidic domain, which spans sequence 220-290 of APP, causes the transmembrane arrest with the COOH-terminal 73-kD portion of the protein facing the cytoplasmic side. Accumulation of full-length APP in the mitochondrial compartment in a transmembrane-arrested form, but not lacking the acidic domain, caused mitochondrial dysfunction and impaired energy metabolism. These results show, for the first time, that APP is targeted to neuronal mitochondria under some physiological and pathological conditions.

Show MeSH
Related in: MedlinePlus