p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization
Abstract
Parkin/PINK1-mediated mitophagy plays a crucial role in the development of Parkinson’s disease (PD). Before damaged mitochondria are removed, Parkin is recruited to the mitochondria, where it promotes mitochondrial clustering. While the mechanism behind PINK1-induced Parkin recruitment to the mitochondria is becoming clearer, the specific function of mitochondrial clustering has remained less understood. In our study, we discovered that the loss of p62, an essential autophagic adaptor protein, disrupted mitochondrial aggregation and increased the susceptibility of Parkin-expressing cells to apoptosis caused by mitochondrial depolarization. Notably, modifying mitochondrial aggregation by regulating p62 or through other methods was sufficient to significantly affect apoptosis outcomes.
Additionally, we found that the disruption of mitochondrial aggregation led to the proteasome-dependent degradation of outer mitochondrial membrane (OMM) proteins, particularly those critical for mitochondrial integrity and function. This degradation accelerated the release of cytochrome c from the mitochondria into the cytoplasm, triggering the intrinsic apoptotic pathway.
Our findings suggest that mitochondrial clustering plays more than a structural role; it actively contributes to preserving mitochondrial integrity. When mitochondrial aggregation was compromised, the mitochondria became more vulnerable to damage, accumulating dysfunctional proteins and losing membrane potential. This loss of membrane integrity increased the likelihood of mitochondrial permeabilization, a hallmark of apoptosis. Furthermore, our results indicate that p62 is vital for maintaining mitochondrial integrity by stabilizing mitochondrial aggregation, potentially acting as a protective mechanism against mitochondrial stress. By preserving the organization of damaged mitochondria, Parkin, in conjunction with p62, helps prevent severe mitochondrial dysfunction, which would otherwise accelerate apoptosis.
Overall, our study highlights the protective role of mitochondrial clustering in mitophagy and underscores its importance in defending cells against stress. These findings provide new insights into the molecular mechanisms underlying Parkinson’s disease, suggesting that enhancing mitophagy or improving mitochondrial function could serve as therapeutic strategies for neurodegenerative diseases. Ultimately, our research enriches the understanding of how processes like mitophagy and P62-mediated mitophagy inducer mitochondrial quality control contribute to neuronal protection in PD and related disorders.