Figure 2.

The role played by the ER and mitochondria in Ca²⁺ homeostasis could contribute to Lewy body (LB) formation and premature death of SNc DA neurons. Ca²⁺ entry through plasma membrane Ca_v1.3 Ca²⁺ channels during activity is either pumped back across the plasma membrane or rapidly sequestered in the ER or mitochondria (Figure 1). Both processes require energy stored in the form of ATP (red ‘ATP’ labels denote ATP requirement). The metabolic demand created by these ATP-dependent steps in Ca²⁺ homeostasis should increase oxidative phosphorylation in mitochondria and the production of damaging ROS. ROS damage mitochondrial proteins such as complex I and mtDNA, reducing the efficiency of oxidative phosphorylation (negative consequences are symbolized by red circles; positive or augmenting consequences are symbolized by red arrows). In extreme cases, the stress on mitochondria induces mPTP opening, swelling and the release of cytochrome c and other pro-apoptotic proteins such as apoptosis-inducing factor (AIF). In parallel, ROS are capable of damaging ER proteins, elevating the concentration of misfolded proteins that need to be degraded by proteasomes and autophagosomes. The unfolded protein response (UPR) triggered by this elevation in misfolded proteins should further reduce ER production of proteins and potentially lead to the release of pro-apoptotic factors such as C/EBP homologous protein (CHOP). The role of mitochondria in Ca²⁺ homeostasis could further compromise their ability to generate ATP, leading to a functionally important drop in cytosolic ATP levels. Such a drop would compromise both ER and proteasome and autophagosome function, also promoting the formation of protein aggregates such as LBs. Genetic mutations (Box 1) or environmental toxins such as rotenone could further compromise mitochondrial or ER function, rendering them more vulnerable to Ca²⁺-induced stress. By hastening the decline in ER and mitochondrial function and the accelerated loss of SNc DA neurons, these genetic and environmental factors could be seen as ‘causing’ PD.