Figure 8

PE activates TFEB to prime mitochondria for efficient mitophagosome formation basally and potentiate PINK1-Parkin mitophagy during mitochondrial stress. PE reduces phosphorylation of TFEB at S142 via a mechanism that depends on cytosolic Ca²⁺. Dephosphorylated TFEB (active TFEB) rapidly translocates to the nucleus, where it mediates transcription of autophagy and lysosomal genes to increase the cellular pools of autophagosomes and lysosomes. The enhanced levels of autophagosomes associate with the mitochondria basally, aided by the “donut-shaped” mitochondrial configuration induced by PE. PE does not promote mitochondrial degradation basally but instead makes mitochondria highly competent to undergo efficient mitophagy when needed. PE primes mitochondria for timely mitophagosome formation in face of severe mitochondrial stress to rapidly remove damaged mitochondria by increasing the recruitment of autophagosomes to mitochondria. Upon onset of mitochondrial stress, PE facilitates the recruitment of PINK1 and Parkin to the mitochondria to initiate PINK1-Parkin dependent mitophagy. This occurrence promotes efficient mitochondrial degradation and quality control during mitochondrial stress to preserve mitochondrial health.