Fig. 2: Interplay between calcium homeostasis and mitophagy.

A At low cytosolic calcium levels, Miro1 facilitates mitochondrial movement by interacting with Milton/TRAK. Increased Ca²⁺ disrupts this interaction, exposing Miro1 to ubiquitination by Parkin and the subsequent PINK1/Parkin-dependent mitophagy upon concurrent mitochondrial stress. B CCCP-induced mitochondrial depolarization triggers the demultimerization of Miro2 from a tetramer to a monomer, a process dependent on PINK1 phosphorylation and Ca²⁺ binding to Miro2 EF2 domain. Miro2 re-alignment stimulates Parkin translocation and mitophagy initiation. C Cytosolic calcium accumulation activates the kinase CAMKIα and the phosphatase CaN which mediate the phosphorylation (Ser600) and dephosphorylation (Ser637) of DRP1, respectively. Both modifications promote mitochondrial translocation of DRP1 which triggers fission, priming mitochondria for mitophagic degradation. D In pancreatic β cells, mitochondrial stress generates ROS that act as signaling molecules for lysosomal calcium release via TRPML channels. Elevated Ca²⁺ activates CaN, which, in turn, dephosphorylates TFEB, enabling its nuclear translocation. In the nucleus, TFEB promotes the expression of the mitophagy adaptor proteins NDP52 and OPTN, among others. Lysosomal calcium stores are primarily replenished from ER. E The key mitophagy factor PINK1 facilitates mitochondrial calcium release by phosphorylating NCLX and LETM1 exchangers, thereby preventing Ca²⁺ overload within mitochondria. PINK1 depletion results in mitochondrial calcium overload, increased ROS generation, mPTP opening and a subsequent rise in cytosolic Ca²⁺ due to diminished mitochondrial buffering capacity. F Examples of Parkin implication in the regulation of calcium homeostasis. Parkin prevents cytosolic calcium overload by ubiquitinating and promoting the proteasomal degradation of PLCγ, the upstream activator of IP3R. CISD1 has been identified as the downstream effector for Parkin-dependent regulation of ER-calcium release. Parkin is proposed to initially enhance ER-mitochondria tethering and mitochondrial Ca²⁺ influx as a means to boost bioenergetics (dashed green arrows). Failure in restoring bioenergetic imbalance enables Parkin’s mitophagy-inducing activity for the elimination of compromised mitochondria (dashed red arrow). Moreover, the cytosolic fraction of Parkin impedes mitochondrial calcium uptake by interacting with MICU1 precursor, enhancing its ubiquitination and subsequent proteasomal degradation. Created in BioRender. Palikaras, K. (2024) https://BioRender.com/r42n942.