Zinc deficiency: An unexpected trigger for autophagy

Abstract

Cells respond to deprivation of certain nutrients such as glucose or nitrogen by inducing autophagy, reclaiming pieces of proteins for use in critical functions. A recent study shows that, in yeast, zinc depletion acts in a similar fashion. Depletion of this essential nutrient induces non-selective autophagy by inhibiting TORC1, leading to release and recycling of zinc from degraded proteins.Non-selective autophagy is like a storm to a cell. Organelles and cytosolic contents are swept up and packaged into doublemembrane vesicles called autophagosomes, delivered to lysosomes/vacuoles, and degraded so component amino acids can be reclaimed for the synthesis of essential new proteins. Multiple nutritional stresses can trigger this storm, including depletion of amino acids, nitrogen, and glucose, but the extent to which other cellular metabolites serve as signals for induction of autophagy remains unclear.Zinc is an important cellular nutrient that plays structural and functional roles in proteins in all organisms (1, 2). As a result, cells have mechanisms to maintain zinc homeostasis when available zinc supplies decrease; in particular, the transcription factor Zap1, the major zinc sensor, responds to limited zinc by increasing the expression of genes such as transporters that increase zinc influx. Autophagy has also been implicated in the cellular response to zinc starvation. In mammalian cells, zinc depletion, for example by zinc chelation, causes a significant suppression of autophagy whereas zinc addition stimulates autophagy in human hepatoma cells across several stimuli (3-7). Although the forecast for other species might be expected to follow this precedent, Kawamata et al. (8) now report the unexpected finding that zinc starvation triggers autophagy in yeast. Kawamata et al. (8) demonstrate that autophagy is robustly activated upon zinc starvation using zinc-depleted media as shown by two autophagic markers, GFP-atg8 and API. Although the time course of activation is delayed compared with the prompt induction of autophagy upon nitrogen starvation, the magnitude of the two responses is comparable. The zinc chelator TPEN (N,N,N,N-tetrakis-[2-pyridyl-methyl]ethylenediamine) also induces autophagy, consistent with zinc starvation causing the observed phenotype. The authors conclude that zinc depletion-induced autophagy is an effort of yeast cells to rescue themselves from zinc starvation-induced growth retardation, as this growth retardation is much worse when autophagy is blocked.The authors provide several additional lines of evidence to confirm that autophagy is caused by a shortage of zinc directly rather than via indirect effects on other nutrients. First, zinc starvation specifically decreases zinc concentrations without lowering the amounts of other divalent cations such as iron and copper. Second, the level of glucose was increased in the zincfree medium. Third, complementation of glucose or other nutrients had no effect on zinc depletion-triggered autophagy, Finally, induction of autophagy by zinc s...

Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn2+ to inhibit cysteinyl cathepsins: review and implications

“…Zn 2 + deficiency induces autophagy and releases sequestered Zn 2 + from degraded cell proteins as investigated in yeast and plants. This restores interactive cell Zn 2 + levels and promotes survival under Zn 2 + deficiency as reported in several recent studies (Eguchi et al 2017; Ding and Zhong 2017; Horie et al 2017; Kawamata et al 2017; Nakatogawa 2018). In theory, release of Zn 2 + from degraded proteins can provide a self-limiting inhibitory effect or “brake” on the rate of Zn 2 + -sensitive protein turnover.…”

Zinc: A Necessary Ion for Mammalian Sperm Fertilization Competency

“…Some of these defects could be due to abnormal testicular function from modulated fatty acid composition, interrupting essential fatty acid metabolism, where ω-6 polyunsaturated fatty acids were highly enriched [176]. Zn 2+ deficiency is known to trigger autophagy in yeast [177], and elevated autophagy rate during spermatogenesis could decrease sperm count during Zn 2+ deficiency. In the absence of fertilization, sperm capacitation is a terminal event leading down a rapid path of apoptosis [178], possibly from the overproduction of ROS [179] in an environment with reduced Zn 2+ .…”

Zinc and Autophagy in Age-Related Macular Degeneration

“…Autophagy is one of the critical cellular reactions to starvation to reclaim parts of proteins to use in life-preserving functions. Starvation is usually due to lack of certain nutrients, such as carbon/glucose or nitrogen, but Kawamata et al were the first to show that zinc deficiency can also be an autophagy trigger in yeast [68,69]. On the other hand, Shinozaki et al recently showed that autophagy maintained zinc pools increased zinc bioavailability and retained ROS homeostasis under zinc deficiency in plants [70].…”