The role of lysososmal biogenesis and the microphthalmia family of transcription factors in Parkin-mediated mitophagy

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NINDS	CELLBIO-10

* FARE Award Winner

Authors

• C.L. Nezich
• A. Fogel
• C. Wang
• R.J. Youle

Abstract

The mitochondrial kinase PINK1 and the cytosolic E3 ligase Parkin regulate a quality-control pathway that selectively eliminates damaged mitochondria via lysosomal-mediated autophagy. Expression of lysosomal and autophagic genes has recently been shown to be regulated by the transcription factor TFEB; however, TFEB has yet to be implicated in any mitochondrial process. Because mitophagy requires robust lysosomal function, we sought to understand the link between mitophagy and lysosomal biogenesis. We found that TFEB translocated to the nucleus and was activated in a Parkin- and PINK1-dependent manner when cells were treated with mitophagy-inducing compounds. Yet unexpectedly, TFEB null cells exhibited no defect in mitophagy and, contrary to previous studies that used RNAi to decrease TFEB levels, elimination of endogenous TFEB had no significant effect on lysosomal morphology. To account for potential compensation for TFEB loss by the other microphthalmia (MiT) transcription factor family members, MITF, TFEC, or TFE3, we generated TFEB/MITF/TFEC/TFE3 quadruple null cells. These cells exhibited a pronounced mitophagy defect, indicating that other members of the MiT family participate in autophagy. Surprisingly, overexpression of TFEC, but not TFEB, MITF, or TFE3, rescued this defect, identifying TFEC as a potential therapeutic target.

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