Fine-tune TMEM11 to unleash basal mitophagy

Abstract

When mitochondrial damage threatens to disrupt cell and tissue homeostasis, selective autophagy (mitophagy) provides an important route to neutralize dysfunctional organelles. Whilst we understand much about stress-induced mitophagy, steady-state and spatial mechanisms remain elusive. In this issue, Gok et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202204021) reveal an unexpected role for TMEM11 in mitophagy regulation.

Figure 1.

Mitochondrial TMEM11 engages BNIP3/NIX to restrain basal mitophagy. Initial studies of TMEM11 localized it to the IMM, and yeast two-hybrid screens identified the mitophagy-associated proteins BNIP3/BNIP3L as putative interactors. The molecular logistics of this association were unclear because of the distinct outer membrane localization of BNIP3/BNIP3L. Gok and colleagues (4) explored the functional roles of TMEM11 and performed a series of converging methods to pinpoint its localization at the OMM. Subsequent proteomics and biochemical profiling revealed the transmembrane domain of TMEM11 interacts with BNIP3/BNIP3L at its respective transmembrane region—which is known to be crucial for mitophagy progression. Strikingly, the authors report that TMEM11 depletion enhances mitophagy levels and leads to abundant BNIP3/BNIP3L microdomains on the OMM. These results identify a new mechanism that could explain differential levels of steady-state (basal) mitophagy. Created with BioRender.com.