Abstract
The mitochondrial presequence translocation machinery (TIM23 complex) is conserved between the yeast Saccharomyces cerevisiae and humans; however, functional characterization has been mainly performed in yeast. Here, we define the constituents of the human TIM23 complex using mass spectrometry and identified ROMO1 as a new translocase constituent with an exceptionally short half-life. Analyses of a ROMO1 knockout cell line revealed aberrant inner membrane structure and altered processing of the GTPase OPA1. We show that in the absence of ROMO1, mitochondria lose the inner membrane YME1L protease, which participates in OPA1 processing and ROMO1 turnover. While ROMO1 is dispensable for general protein import along the presequence pathway, we show that it participates in the dynamics of TIM21 during respiratory chain biogenesis and is specifically required for import of YME1L. This selective import defect can be linked to charge distribution in the unusually long targeting sequence of YME1L. Our analyses establish an unexpected link between mitochondrial protein import and inner membrane protein quality control.
Highlights
Mitochondria are of central importance for the metabolism of eukaryotic cells such as the generation of ATP by oxidative phosphorylation
While ROMO1 is dispensable for general import, we find that it is required for the recruitment of TIM21 to the translocation machinery
ROMO1 was speculated to be related to yeast TIM23 complex subunit Mgr2 (Fig. S1 A; Žárský and Doležal, 2016)
Summary
Mitochondria are of central importance for the metabolism of eukaryotic cells such as the generation of ATP by oxidative phosphorylation. OPA1 is processed by the ATP-dependent YME1L protease and the zinc metalloprotease OMA1 (Ishihara et al, 2006; Song et al, 2007; Anand et al, 2014). These proteases balance long (L)-OPA1 and short (S)-OPA1 forms. YME1L facilitates the turnover of a number of inner membrane and intermembrane space proteins, such as the translocase components TIM23 and TIM17A (Rainbolt et al, 2013; Wai et al, 2016) and the lipid transfer proteins PRELID1 and STARD7 (Potting et al, 2013; Saita et al, 2018) and is important for mitochondrial protein quality
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