Mitochondrial trafficking of APP and alpha synuclein: Relevance to mitochondrial dysfunction in Alzheimer's and Parkinson's diseases.
Mitochondrial dysfunction is an important intracellular lesion associated with a wide variety of diseases including neurodegenerative disorders. In addition to aging, oxidative stress and mitochondrial DNA mutations, recent studies have implicated a role for the mitochondrial accumulation of proteins such as plasma membrane associated amyloid precursor protein (APP) and cytosolic alpha synuclein in the pathogenesis of mitochondrial dysfunction in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. Both of these proteins contain cryptic mitochondrial targeting signals, which drive their transport across mitochondria. In general, mitochondrial entry of nuclear coded proteins is assisted by import receptors situated in both outer and inner mitochondrial membranes. A growing number of evidence suggests that APP and alpha synclein interact with import receptors to gain entry into mitochondrial compartment. Additionally, carboxy terminal cleaved product of APP, approximately 4 kDa Abeta, is also transported into mitochondria with the help of mitochondrial outer membrane import receptors. This review focuses on the mitochondrial targeting and accumulation of these two structurally different proteins and the mode of mechanism by which they affect the physiological functions of mitochondria.
Devi
Latha
L
Department of Animal Biology, School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104, USA.
Anandatheerthavarada
Hindupur K
HK
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D051336:Mitochondrial Membranes / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D021381:Protein Transport / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D051844:alpha-Synuclein