Figure 2.

MERCS in health and in PD. In healthy controls (upper part of the figure), different functions of MERCS are integrated to maintain cell homeostasis. The IP3Rs-Grp75-VDAC1 complex together with the MCU complex allows the entry of Ca²⁺ into mitochondria, where it can boost the TCA cycle, inducing ATP production. This complex, together with Mfn2, can also modulate the connectivity between the ER and mitochondria. Under normal conditions, PINK1 is imported into mitochondria, where it can be degraded by PARL and MPP. In cases where mitochondria are damaged, PINK1 import is unsuccessful, and this protein accumulates in the OMM, where it recruits Parkin. Parkin then ubiquitinates proteins at the OMM, inducing mitophagy. In familial PD, mutation in α-synuclein (αS in the figure) increases MERCS, inducing Ca²⁺ overflow inside mitochondria. However, PD-related mutations in DJ-1 (mDJ-1), α-synuclein (mαS), PINK1, Parkin and LRKK2 led to a decrease in MERCS. Nevertheless, these mutations lead to mitochondrial dysfunction, including mitochondrial stress and decreased ATP production as well as ER stress. PD mutations in PINK1 and Parkin (mPINK1 and mParkin in the figure) are usually associated with loss of function and therefore lead to impaired mitophagy activation, preventing the clearance of damaged mitochondria. Different colours correspond to proteins involved in different cellular processes and faded colours as well as dashed lines represent the downregulation of the process or protein level/function. Red arrows as well as red cross correspond to blocked/impaired process.