How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.

Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently elicit mitophagy without the loss of mitochondrial membrane potential.

Fine-Tuning TOM-Mitochondrial Import via Ubiquitin.

Given their polyvalent functions, an inherent challenge that mitochondria face is the exposure to mitochondrial import stresses, culminating in their dysfunction. Recently, mitochondrial import of several mitochondrial substrates was shown to be regulated via a 'tug of war' between USP30 and MARCH5, two ubiquitin-related enzymes located at the TOM complex.

Beyond ER: Regulating TOM-Complex-Mediated Import by Ubx2.

Despite the progress in understanding the molecular responses to mitochondrial damage, responses to aberrant accumulation of mitochondrial precursor proteins and mitochondrial import defects remain poorly understood. Recent work (Mårtensson et al., Nature, 2019) has unveiled a pathway similar to endoplasmic-reticulum-associated degradation (ERAD) in fine-tuning the fidelity of translocase of the outer mitochondrial membrane (TOM) complex-mediated mitochondrial import.

Cell Death: N-degrons Fine-Tune Pyroptotic Cell Demise.

The N-end rule pathway mediates the degradation of proteins through their destabilizing amino-terminal residues. While previously implicated in apoptosis regulation, N-end rule degradation has now recently been shown to fine-tune pyroptotic cellular demise through the amino-terminal degradation of the inflammasome component NLRP1B.

Formylation of Eukaryotic Cytoplasmic Proteins: Linking Stress to Degradation.

Unlike prokaryotes, N-terminal formylation has been confined to a handful of mitochondrial proteins in eukaryotes. A recent study unveils a new role for eukaryotic cytoplasmic N-terminal formylation linking diverse cellular stresses to N-terminal-dependent protein degradation. These findings suggest broad cellular implications in higher eukaryotes for N-terminal methionine formylation.

Ataxin-3 deubiquitination is coupled to Parkin ubiquitination via E2 ubiquitin-conjugating enzyme.

We reported previously that parkin, a Parkinson disease-associated E3 ubiquitin-ligase interacts with ataxin-3, a deubiquitinating enzyme associated with Machado-Joseph disease. Ataxin-3 was found to counteract parkin self-ubiquitination both in vitro and in cells. Moreover, ataxin-3-dependent deubiquitination of parkin required the catalytic cysteine 14 in ataxin-3, although the precise mechanism remained unclear.