The role of calcium signalling in autophagy

• Main Author: Chehab, Tala
• Published: Open University 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748592

Autophagy is a catabolic process that is important for degradation of cellular components, and for cell survival, and has also been associated with pathological disorders and tumour growth. Autophagy is a complex process; many factors and messengers converge to control steps along the autophagic pathway. Ca²⁺ has been proposed to regulate autophagy. However, Ca²⁺ has been proposed to be both pro- and anti-autophagic. To better understand how Ca²⁺ has these opposing effects, this study investigated in what ways particular sources of Ca²⁺, and the characteristics of Ca²⁺ signals impacted on autophagy. The fundamental need for Ca²⁺ in the activation of autophagy was demonstrated by loading cells with an exogenous Ca²⁺ buffer, which prevented various stimuli from triggering autophagy. Autophagy could be activated by inhibiting the transfer of Ca²⁺ from the endoplasmic reticulum to the mitochondrial matrix. This was achieved by expressing an enzyme that prevented Ca²⁺ release from inositol 1,4,5-trisphosphate receptors, inhibition of mitochondrial respiration, and knockdown of the mitochondrial Ca²⁺ uniporter. The triggering of autophagy under these conditions was due to reduced cellular ATP levels. These data suggest that Ca²⁺ signals arising from InsP₃Rs suppress autophagy. Additional studies used a well-characterised Ca²⁺ transport pathway to generate cellular Ca²⁺ signals, and examined their ability to trigger autophagy. This pathway, known as ‘store-operated Ca²⁺ entry’ (SOCE), was activated by depleting endoplasmic reticulum Ca²⁺ stores using inhibitors of sarco/endoplasmic reticulum ATPases (SERCA). It was found that sustained cellular Ca²⁺ signals arising via chronic inhibition of SERCA were pro-autophagic. The activation of autophagy absolutely required the presence of extracellular Ca²⁺, and was not due to cellular stress. Using pharmacological inhibition of various Ca²⁺-sensitive kinases, it was found that at least part of the autophagy that occurred during SOCE was due to activation of Ca²⁺/calmodulin-dependent kinase kinase-β (CaMKK-β, also known as CaMKK-2).