The Role of Calcium Signalling in Autophagy

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. <br></br><br></br>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. <br></br><br></br> 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. <br></br><br></br> 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).

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2018

Author dc:creator

• Chehab, Tala

Language dc:language

en