Abstract
Mitochondria are key players of cellular metabolism, Ca2+ homeostasis, and apoptosis. The functionality of mitochondria is tightly regulated, and dysfunctional mitochondria are removed via mitophagy, a specialized form of autophagy that is compromised in hereditary forms of Parkinson's disease. Through mitophagy, cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of pro-apoptotic BCL-2 family proteins located on the outer mitochondrial membrane. Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases (caspases). We are only beginning to understand how the choice between mitophagy and the activation of caspases is determined on the mitochondrial surface. Intriguingly in neurons, caspase activation also plays a non-apoptotic role in synaptic plasticity. Here we review the current knowledge on the interplay between mitophagy and caspase activation with a special focus on the central nervous system.
Highlights
In neurons, a functioning mitochondrial quality control system is of particular importance as they depend more than other cell types on a healthy pool of mitochondria due to high energy demand and importance of Ca2+ buffering
Cells are able to cope with mitochondrial stress until the damage becomes too great, which leads to the activation of proapoptotic B-cell lymphoma 2 (BCL-2) family proteins located on the outer mitochondrial membrane
Active pro-apoptotic BCL-2 proteins facilitate the release of cytochrome c from the mitochondrial intermembrane space (IMS) into the cytosol, committing the cell to apoptosis by activating a cascade of cysteinyl-aspartate specific proteases
Summary
A functioning mitochondrial quality control system is of particular importance as they depend more than other cell types on a healthy pool of mitochondria due to high energy demand and importance of Ca2+ buffering. Mutations in PINK1 and Parkin, two proteins involved in the removal of damaged mitochondria, cause familiar autosomal recessive PD, underlining the importance of a functioning mitochondrial quality control system in neurons (Kitada et al 1998; Valente et al 2004). PINK1 is transported into mitochondria due to its N-terminal mitochondrial targeting sequence via the translocase of the outer membrane (TOM) and the translocase of the inner membrane (TIM) complexes (Silvestri et al 2005) This import is favored by the interaction of the phosphorylated TOM receptor TOM22 and the PINK1 precursor (Kravic et al 2018). The accumulation of phosphorylated ubiquitin chains on damaged mitochondria in turn results in further recruitment and activation of Parkin creating a positive feedback loop that drives mitophagy (Okatsu et al 2015; Ordureau et al 2014). Defects in the mitophagic process likely contribute to the pathogenesis of PD due to accumulation of damaged mitochondria eventually leading to cell death
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