Calcium Homeostasis in the Control of Mitophagy

Significance: Maintenance of mitochondrial quality is essential for cellular homeostasis. Among processes responsible for preserving healthy mitochondria, mitophagy selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Alterations in mitophagy lead to the accumulation of damaged mitochondria, which plays an essential role in several diseases such as carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies. Recent Advances: Calcium (Ca²⁺) plays a fundamental role in cell life, modulating several pathways, such as gene expression, proliferation, differentiation, metabolism, cell death, and survival. Indeed, because it is involved in all these events, Ca²⁺ is the most versatile intracellular second messenger. Being a process that limits cellular degeneration, mitophagy participates in cellular fate decisions. Several mitochondrial parameters, such as membrane potential, structure, and reactive oxygen species, can trigger the activation of mitophagic machinery. These parameters regulate not only mitophagy but also the mitochondrial Ca²⁺ uptake. Critical Issues: Ca²⁺ handling is fundamental in regulating ATP production by mitochondria and mitochondrial quality control processes. Despite the growing literature about the link between Ca²⁺ and mitophagy, the mechanism by which Ca²⁺ homeostasis regulates mitophagy is still debated. Future Directions: Several studies have revealed that excessive mitophagy together with altered mitochondrial Ca²⁺ uptake leads to different dysfunctions in numerous diseases. Thus, therapeutic modulation of these pathways is considered a promising treatment. Antioxid. Redox Signal. 38, 581-598.