Then, LRPPRC, Parkin and other substrates of Parkin may be ubiquitinated by Parkin E3 ligase and recognized by autophagy machinery and guide mitochondria to be degraded through mitophagy. Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. Mitofusin 1, Drp1 and VDAC1 were reported to be substrates of Parkin while LRPPRC is also listed as Parkin substrates in the MG132 associated online supplementary although the exact mechanism is still in investigation. Ubiquitinated VDAC1 and Drp1 will cause their associated mitochondria to be brought into autophagosomes and autolysosomes for degradation. Since a significant portion of Bcl-2 is associated with mitochondria and Parkin-mono-ubiquitinated Bcl2 is more stable, suppression of LRPPRC leads to decreases in levels of Parkin and Bcl-2 and activation of basal autophagy as we previous reported. Interestingly, Parkin itself is the substrate of its ligase activity. After auto-ubiquitination, Parkin gradually becomes depleted along Bcl-2 and ATG5-ATG12 conjugate in cells under long-term mitophagy stress. The drug-induced mitophagy stress is an artificially introduced pathological condition. Under normal physiological condition, it is unlikely that all of mitochondria in cells are simultaneously damaged. The drug-induced mitochondrial damages are so massive that autophagy/mitophagy machinery is incapable of handing so many damaged mitochondria immediately. This is possibly the reason that we observed a large Nilotinib amount of mitochondria aggregates accumulated in the first 12 hrs after exposure to mitophagy inducer. These mitochondrial aggregates then become fragmented mitochondria to be engulfed in autophagosomes and further autolysosomes for degradation. Parkinson’s disease results from the death of dopaminecontaining cells in the substantia nigra region of the midbrain. Several mutations in specific genes such as Parkin have been identified in a few individuals with familial form or autosomal recessive juvenile Parkinson’s disease. Mitochondrial dysfunction and oxidative stress have long been implicated as the general pathophysiologic mechanisms underlying Parkinson’s disease. Impairment of autophagy and mitophagy processes may be the determining force in the majority of patients to develop Parkinson’s disease. Interestingly, the same group of proteins involved in juvenile Parkinson’s disease also plays important roles in tumorigenesis although the somatic mutations of Parkin identified are homozygous in Parkinson’s disease and heterozygous in cancers. If the autophagic process is blocked before autophagosomal formation, the fragmented mitochondria will release cytochrome c and other molecules to induce apoptosis that is usually associated with diverse forms of aggregation and perinuclear clustering of the dysfunctional mitochondria. If either the process is blocked before the autolysosomal formation or autophagosomes are not degraded efficiently, the accumulated mitochondria may become damaged by their own production of superoxide and start to leak electrons and lose their membrane potentials, and even further induce robust oxidative stress. High levels of oxidative stress are lethal in post-mitotic neuronal cells in Parkinson’s disease, while sub-lethal levels of oxidative stress not only induces DNA double-strand breaks but also weakens mitotic checkpoint function so that cells carrying damaged genomes can escape mitotic checkpoint to enter next rounds of mitosis to further destabilize the genomes and result in tumorigenesis. High levels of LRPPRC maintain Bcl-2 levels, block mitophagy and prevent mitochondria from autophagy degradation.