Regulation of mammalian autophagy in physiology and pathophysiology.
(Macro)autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles. Autophagy is initiated by double-membraned structures, which engulf portions of cytoplasm. The resulting autophagosomes ultimately fuse with lysosomes, where their contents are degraded. Although the term autophagy was first used in 1963, the field has witnessed dramatic growth in the last 5 years, partly as a consequence of the discovery of key components of its cellular machinery. In this review we focus on mammalian autophagy, and we give an overview of the understanding of its machinery and the signaling cascades that regulate it. As recent studies have also shown that autophagy is critical in a range of normal human physiological processes, and defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, cancers, and Crohn's disease, we discuss the roles of autophagy in health and disease, while trying to critically evaluate if the coincidence between autophagy and these conditions is causal or an epiphenomenon. Finally, we consider the possibility of autophagy upregulation as a therapeutic approach for various conditions.
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom.
Brinda
B
Ravikumar
Sovan
S
Sarkar
Janet E
JE
Davies
Marie
M
Futter
Moises
M
Garcia-Arencibia
Zeyn W
ZW
Green-Thompson
Maria
M
Jimenez-Sanchez
Viktor I
VI
Korolchuk
Maike
M
Lichtenberg
Shouqing
S
Luo
Dunecan C O
DC
Massey
Fiona M
FM
Menzies
Kevin
K
Moreau
Usha
U
Narayanan
Maurizio
M
Renna
Farah H
FH
Siddiqi
Benjamin R
BR
Underwood
Ashley R
AR
Winslow
David C
DC
Rubinsztein
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D005057:Eukaryotic Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008322:Mammals / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological