FKBP8 recruits LC3A to mediate Parkin‐independent mitophagy

Abstract

Mitophagy, the selective removal of damaged or excess mitochondria by autophagy, is an important process in cellular homeostasis. The outer mitochondrial membrane ( OMM ) proteins NIX , BNIP 3, FUNDC 1, and Bcl2‐L13 recruit ATG 8 proteins ( LC 3/ GABARAP ) to mitochondria during mitophagy. FKBP 8 (also known as FKBP 38), a unique member of the FK 506‐binding protein ( FKBP ) family, is similarly anchored in the OMM and acts as a multifunctional adaptor with anti‐apoptotic activity. In a yeast two‐hybrid screen, we identified FKBP 8 as an ATG 8‐interacting protein. Here, we map an N‐terminal LC 3‐interacting region ( LIR ) motif in FKBP 8 that binds strongly to LC 3A both in vitro and in vivo . FKBP 8 efficiently recruits lipidated LC 3A to damaged mitochondria in a LIR ‐dependent manner. The mitophagy receptors BNIP 3 and NIX in contrast are unable to mediate an efficient recruitment of LC 3A even after mitochondrial damage. Co‐expression of FKBP 8 with LC 3A profoundly induces Parkin‐independent mitophagy. Strikingly, even when acting as a mitophagy receptor, FKBP 8 avoids degradation by escaping from mitochondria. In summary, this study identifies novel roles for FKBP 8 and LC 3A, which act together to induce mitophagy. image FKBP 8 (also called FKBP 38) is a novel mitophagy receptor that selectively recruits LC 3A to damaged mitochondria to mediate Parkin‐independent degradation of mitochondria by autophagy. The anti‐apoptotic FKBP 8 itself escapes degradation to ensure cell survival. FKBP 8 binds to LC 3A via an N‐terminal LIR motif. FKBP 8 recruits lipidated LC 3A to damaged mitochondria in a Parkin‐independent manner. Co‐expression of FKBP 8 and LC 3A induces efficient Parkin‐independent mitophagy. FKBP 8 escapes from the mitochondria destined for autophagic degradation after having recruited LC 3A.