Regulation of autophagy and mitophagy by nutrient availability and acetylation

Abstract

Normal cellular function is dependent on a number of highly regulated homeostatic mechanisms, which act in concert to maintain conditions suitable for life. During periods of nutritional deficit, cells initiate a number of recycling programs which break down complex intracellular structures, thus allowing them to utilize the energy stored within. These recycling systems, broadly named “autophagy”, enable the cell to maintain the flow of nutritional substrates until they can be replenished from external sources. Recent research has shown that a number of regulatory components of the autophagy program are controlled by lysine acetylation. Lysine acetylation is a reversible post-translational modification that can alter the activity of enzymes in a number of cellular compartments. Strikingly, the main substrate for this modification is a product of cellular energy metabolism: acetyl-CoA. This suggests a direct and intricate link between fuel metabolites and the systems which regulate nutritional homeostasis. In this review, we examine how acetylation regulates the systems that control cellular autophagy, and how global protein acetylation status may act as a trigger for recycling of cellular components in a nutrient-dependent fashion. In particular, we focus on how acetylation may control the degradation and turnover of mitochondria, the major source of fuel-derived acetyl-CoA.

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins

“…Nonetheless, a growing number of studies using site-directed mutagenesis strategies show that at least some of these modifications alter activity of mitochondrial proteins, mostly in a negative direction (Hallows et al, 2006; Hallows et al, 2011; Hirschey et al, 2010; Still et al, 2013), although gain-of-function acetylation events have been reported (Fernandes et al, 2015; Lu et al, 2015). Lysine acetylation has also been linked to nutrient control of autophagy and mitophagy (Webster et al, 2014). Although these processes appear to be regulated by acetylation of specific proteins that reside outside the mitochondrial matrix, including some that localize to the outer mitochondrial membrane, the current findings suggest hyperacetylation of the matrix proteome might have a reciprocal effect on AcK events in other compartments.…”

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

“…Laboratory studies consistent with fasting compliance included findings of low glucose and insulin levels at the time of fasting and induction of glucose and insulin and suppression of growth horInterestingly, intermittent fasting and caloric restriction, which can counter the effects of obesity, also confer beneficial effects against canonical NLRP3 inflammation-linked pathologies, such as insulin resistance and asthma (19)(20)(21). As the nutrient-sensing NAD-dependent lysine deacetylase sirtuin proteins are activated by fasting/caloric restriction (22,23), ameliorate nutrient excess-linked pathology (24,25), and can enhance mitochondrial integrity (26,27), we reasoned that intermittent fasting amelioration of inflammation may be mediated, in part, via sirtuin-regulated mitochondrial quality control, with subsequent blunting of the NLRP3 inflammasome.…”

Regulation of hypometabolism: insights into epigenetic controls

“…This might be one way to extend protein lifespan during hypometabolism because net rates of both protein synthesis and protein degradation are known to be suppressed as part of metabolic rate depression, as occurs in anoxia tolerance in turtles (Hochachka et al, 1996;Storey and Storey, 2007). New work has also linked lysine acetylation with the control of autophagy, a process that is triggered by periods of nutritional deficit during which cells initiate recycling programmes to break down expendable intracellular structures and catabolize them for energy (Webster et al, 2014). Note that autophagy is a known component of dauer formation in C. elegans, a hypometabolic state induced by nutrient restriction (Meléndez et al, 2003).…”