Figure 2. Schematic diagram highlighting a proposed framework for the roles of PINK1, Parkin and Omi/HtrA2 in mediating mitochondrial homeostasis.
PINK1 directly or indirectly promotes phosphorylation of TRAP1, HtrA2 and parkin, resulting in activation of both localized and organelle level responses to promote neuronal cell survival.
(1) A mild to modest localized stress to mitochondrial proteins (one yellow bolt) activates the PINK1-TRAP1 and PINK1-Omi/HtrA2 pathways, stabilizing the mitochondrial cytoarchitecture in response to oxidative stress and heat shock. Another response to localized outer membrane damage may involve tagging of damaged proteins for proteasomal degradation by ubiquitin ligases including Parkin, Mitochondrial fusion may act to stabilize membrane potential, diluting damaged DNA or other components.
(2) More extensive damage from persistent mitochondrial ROS (two yellow bolts) may be caused by loss of PINK1 function and/or environmental toxins, leading to compensatory increases in Parkin expression and mitochondrial fission. Parkin participates in a parallel pro-survival pathway, compensating for damaged mitochondrial by driving selective autophagy of depolarized segments isolated by mitochondrial fission. This may also serve to limit release of apoptogenic intermembrane space proteins.
(3) Successful neuronal adaptation to stress employing either of these parallel pathways would require effective transcriptional responses and reassembly of functional mitochondrial components. Nuclear encoded proteins are essential for both mitochondrial DNA replication (POLG) and transcription of mitochondrially encoded genes (POLRMT, TFAM, etc), along with coordinated synthesis, import and processing or assembly of nuclear encoded mitochondrial proteins.
Under conditions of PINK1 loss of function, alternative means to activate mitochondrial quality control pathways may serve to compensate for increased mitochondrial injury, although likely at a greater bioenergetic cost.