Abstract
Multiple mitochondrial quality control pathways exist to maintain the health of mitochondria and ensure cell homeostasis. Here, we investigate the role of the endosomal adaptor Tollip during the mitochondrial stress response and identify its interaction and colocalisation with the Parkinson's disease‐associated E3 ubiquitin ligase Parkin. The interaction between Tollip and Parkin is dependent on the ubiquitin‐binding CUE domain of Tollip, but independent of Tom1 and mitophagy. Interestingly, this interaction is independent of Parkin mitochondrial recruitment and ligase activity but requires an intact ubiquitin‐like (UBL) domain. Importantly, Tollip regulates Parkin‐dependent endosomal trafficking of a discrete subset of mitochondrial‐derived vesicles (MDVs) to facilitate delivery to lysosomes. Retromer function and an interaction with Tom1 allow Tollip to facilitate late endosome/lysosome trafficking in response to mitochondrial stress. We find that upregulation of TOM20‐positive MDVs upon mitochondrial stress requires Tollip interaction with ubiquitin, endosomal membranes and Tom1 to ensure their trafficking to the lysosomes. Thus, we conclude that Tollip, via an association with Parkin, is an essential coordinator to sort damaged mitochondrial‐derived cargo to the lysosomes.
Highlights
Mitochondrial quality control pathways are essential to maintain their proper function and ensure overall cell health and survival
To allow for the identification of both the mitochondrial network and cargo-selective mitochondrial-derived vesicles (MDVs) (Neuspiel et al, 2008; McLelland et al, 2014), mitochondria were co-labelled for TOM20 and the pyruvate dehydrogenase complex (PDH) E2/E3 bp subunits, proteins localised to the mitochondrial outer membrane (MOM) and mitochondrial matrix, respectively (Fig 1B)
This identification of a Tollip/Parkin axis in MDV trafficking elucidates several key mechanisms regulating mitochondrial quality control, which may suggest further unidentified Parkin substrates are modulated at more discrete levels compared with previously defined targets by cargo-selective mechanisms to facilitate their trafficking to the lysosome
Summary
Mitochondrial quality control pathways are essential to maintain their proper function and ensure overall cell health and survival. More recent data have highlighted that a number of alternative mitochondrial quality control pathways exist that require distinct membrane sources and are separate from canonical mitophagy (Xu et al, 2011; Soubannier et al, 2012; Abeliovich et al, 2013; McLelland et al, 2014, 2016; Lazarou et al, 2015; Hughes et al, 2016; Burman et al, 2017; Chakraborty et al, 2018; Di Rita et al, 2018; Rakovic et al, 2018) To date, it is not understood whether these distinct pathways function in parallel nor the extent of their conservation of mechanisms
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