Ca2+ in quality control: an unresolved riddle critical to autophagy and mitophagy

Calcium (Ca (2+)) has long been known as a ubiquitous intracellular second messenger, exploited by cells to control processes as diverse as development, proliferation, learning, muscle contraction and secretion. The spatial and temporal patterns of these Ca (2+)-associated signals, as well as their amplitude, is precisely controlled to create gradients of the ion, varying considerably depending on cell type and function. Tuning of intracellular Ca (2+) is achieved in part by the buffering role of mitochondria, whose unperturbed function is essential for maintaining cellular energy balance. Quality of mitochondria is ensured by the process of targeted autophagy or mitophagy, which depends on a molecular cascade driving the catabolic process of autophagy toward damaged or deficient organelles for elimination via the lysosomal pathway. Nonspecific and targeted autophagy are highly regulated processes fundamental to cell growth and tissue homeostasis, allowing resources to be reallocated in nutrient-deprived cells as well as being instrumental in the repair of damaged organelles or the elimination of those in excess. Given the role of Ca (2+) signaling in many fundamental cellular processes requiring precise regulation, the involvement of Ca (2+) in autophagy is still somewhat ill-defined, and only in the past few years has evidence emerged linking the two. This mini-review aims to summarize recent work implicating Ca (2+) as an important regulator of autophagy, outlining a role for Ca (2+) that may be even more critical in the regulation of targeted mitochondrial autophagy.