ReviewMetabolism

Target acquired: Selective autophagy in cardiometabolic disease

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Sci. Signal.  28 Feb 2017:
Vol. 10, Issue 468, eaag2298
DOI: 10.1126/scisignal.aag2298

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GLOSS

The accumulation of damaged or excess proteins and organelles is a defining feature of cardiometabolic diseases such as diabetes, atherosclerosis, and heart failure. One way in which damaged components such as mitochondria, protein aggregates, or peroxisomes are degraded is through autophagy, a process in which a double-membrane vesicle encapsulates cargo and delivers it to the acidic lysosome for degradation. A diverse array of molecular mechanisms target the autophagic machinery specifically to damaged cargo and spare healthy components in a process called selective autophagy. Disruption of these processes leads to accumulation of unhealthy organelles, oxidative stress, inflammation, and disease progression. Conversely, stimulating the autophagy-lysosomal degradation system in disease states featuring overt accumulation of dysfunctional organelles provides an attractive avenue for therapies. In this Review, which contains 6 figures, 1 table, and 252 citations, we focus on emerging evidence and key questions about the role of selective autophagy in the cell biology and pathophysiology of cardiometabolic diseases.

Abstract

The accumulation of damaged or excess proteins and organelles is a defining feature of metabolic disease in nearly every tissue. Thus, a central challenge in maintaining metabolic homeostasis is the identification, sequestration, and degradation of these cellular components, including protein aggregates, mitochondria, peroxisomes, inflammasomes, and lipid droplets. A primary route through which this challenge is met is selective autophagy, the targeting of specific cellular cargo for autophagic compartmentalization and lysosomal degradation. In addition to its roles in degradation, selective autophagy is emerging as an integral component of inflammatory and metabolic signaling cascades. In this Review, we focus on emerging evidence and key questions about the role of selective autophagy in the cell biology and pathophysiology of metabolic diseases such as obesity, diabetes, atherosclerosis, and steatohepatitis. Essential players in these processes are the selective autophagy receptors, defined broadly as adapter proteins that both recognize cargo and target it to the autophagosome. Additional domains within these receptors may allow integration of information about autophagic flux with critical regulators of cellular metabolism and inflammation. Details regarding the precise receptors involved, such as p62 and NBR1, and their predominant interacting partners are just beginning to be defined. Overall, we anticipate that the continued study of selective autophagy will prove to be informative in understanding the pathogenesis of metabolic diseases and to provide previously unrecognized therapeutic targets.

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