Mitochondrial Ca2+ signals in autophagy
Introduction
Autophagy, a lysosomal degradation pathway that is conserved from yeast to humans, plays an important role in degrading and recycling cellular constituents, including damaged organelles. It operates as a bulk degradation system in all cells as a complementary system to the ubiquitin–proteasome degradation pathway [1]. At least three types of autophagy have been described according to their lysosomal delivery mechanisms: microautophagy, chaperone-mediated autophagy and macroautophagy [2]. Among these, macroautophagy is the only one that has been observed to date to be regulated by Ca2+ [3] and will therefore be the focus of this review. Macroautophagy involves the formation of a double membrane cistern, possibly derived from several sources including endoplasmic reticulum [4] and mitochondria [5], that enlarges and fuses with itself, engulfing cytoplasmic constituents within an autophagosome in a process involving an evolutionary set of over 20 conserved proteins (known as Atg proteins) essential for the execution of autophagy [1], [6]. Autophagosomes fuse with late endosomes and lysosomes, promoting the delivery of organelles, aggregated proteins and cytoplasm to the luminal acidic degradative milieu that enables their breakdown into constituent molecular building blocks that can be recycled by the cell [1]. Macroautophagy is a bulk cytoplasmic degradation pathway, but under some situations it appears to operate in an organelle-selective way, for example towards mitochondria, referred to as mitophagy, and the endoplasmic reticulum, referred to as reticulophagy [7]. Macroautophagy, hereafter referred to as autophagy, plays different cellular roles depending on physiological context. In unstressed cells, low rates of autophagy perform a housekeeping function, termed quality control autophagy, that is essential for maintenance of normal cellular homeostasis [8]. Autophagy also has important roles in cellular responses to certain invading pathogens including bacteria and viruses [2], and it also functions in developmental cell death, tumor suppression, and aging, and it has been implicated in neurodegeneration, cardiovascular disease and cancer [1], [9]. Under conditions of stress, most famously starvation, autophagy is strongly activated as a pro-survival mechanism by promoting the recycling of fatty acids and amino acids to meet cellular metabolic demands, either through synthesis of new macromolecules or by their oxidation in mitochondria to maintain cellular ATP and viability until nutrient supplies are restored [10]. Autophagy has also been implicated in cell death, referred to as programmed cell death type II [11]. However, because there is little direct evidence for autophagy as the primary driver of cell death under (patho)physiological conditions, it has been referred to as cell death “with autophagic features” [12].
Section snippets
mTOR dependent autophagy and cytoplasmic calcium
A number of protein complexes and signaling pathways are involved in the initiation of autophagy, the maturation of autophagosomes, and their delivery to and fusion with lysosomes [1], [13]. The central player in the regulation of autophagy, representing the canonical pathway of autophagy activation, is the mammalian target of rapamycin (mTOR), specifically the complex 1 (mTORC1) [14], [15]. mTORC1 is a serine-threonine kinase that plays important roles in regulating cell growth, cell cycle
mTOR independent autophagy and InsP3R Ca2+ signaling
Ca2+ signaling has also been linked to non-canonical, mTOR-independent autophagy. In a seminal study, Sarkar et al. observed that lithium (Li+) stimulates autophagy in an mTOR-independent manner by inhibiting inositol monophosphatase (IMPase), the enzyme responsible for maintaining cellular levels of free inositol required for phosphatidylinositol signaling [41]. Li+ activation of autophagy could be reversed by manipulations that raised cytoplasmic InsP3 levels, implicating phosphatidylinositol
Calcium signals and mitochondria
AMPK is a highly sensitive indicator of cellular energy status, whose activity increases under conditions of metabolic stress that elevate the cytoplasmic AMP:ATP ratio [20]. Treatment of hepatocytes with XeB increased AMP levels and the AMP:ATP ratio [37]. The presence of elevated [AMP] and the requirement for AMPK activation to induce pro-survival autophagy in response to loss of InsP3R Ca2+ signaling suggested that cells lacking this pathway have compromised bioenergetics. In agreement,
Essential regulation of cell bioenergetics by constitutive InsP3R Ca2+ transfer to mitochondria
Elevated [AMP] and the requirement for AMPK activation to induce pro-survival autophagy in response to loss of InsP3R Ca2+ signaling suggests that cells lacking this pathway have compromised bioenergetics. In a simple model, constitutive low-level InsP3R-mediated Ca2+ transfer to mitochondria promotes oxidative phosphorylation, and cells lacking this pathway have diminished bioenergetics that are sensed by AMPK that activates autophagy. In agreement, incubating cells with methyl-pyruvate that
Summary
In summary, an essential cellular process that is required for efficient mitochondrial respiration and maintenance of normal cell bioenergetics involves constitutive Ca2+ transfer from the ER to mitochondria mediated by the InsP3R (Fig. 2). In the absence of this ongoing uptake of Ca2+ by mitochondria, oxidative phosphorylation is reduced, lowering cellular levels of ATP. This bioenergetic deficit is sensed by AMPK, which in turn activates autophagy as a survival mechanism. Activation of
Acknowledgements
The authors acknowledge financial support from the National Institutes of Health (GM/DK56328 to JKF) and FONDECYT (1120443 to CC). CC was supported by an award from the American Heart Association.
References (89)
- et al.
A dual role for Ca2+ in autophagy regulation
Cell Calcium
(2011) - et al.
Mitochondria supply membranes for autophagosome biogenesis during starvation
Cell
(2010) - et al.
Autophagy in the pathogenesis of disease
Cell
(2008) - et al.
mTOR regulation of autophagy
FEBS Lett.
(2010) - et al.
Thinking globally and acting locally with TOR
Curr. Opin. Cell Biol.
(2006) - et al.
Growing roles for the mTOR pathway
Curr. Opin. Cell Biol.
(2005) - et al.
TOR signaling in growth and metabolism
Cell
(2006) - et al.
Growth factor regulation of autophagy and cell survival in the absence of apoptosis
Cell
(2005) - et al.
TSC2 mediates cellular energy response to control cell growth and survival
Cell
(2003) - et al.
AMP-activated protein kinase and the regulation of autophagic proteolysis
J. Biol. Chem.
(2006)