Mitochondrial precursor processing represents the crucial maturation step following the import of nuclear-encoded proteins into mitochondria. Whereas the majority of mitochondrial proteins use cleavable N-terminal presequences as targeting signals for import in yeast3, comprehensive, high-confidence data for the human mitochondrial proteome are lacking. To gain initial insights into the landscape of presequence-containing proteins in human cells, we subjected the complete human proteome to two widely used mitochondrial targeting prediction algorithms, MitoFates and TargetP18,19 (Extended Data Fig. 1a and Supplementary Table 1). MitoFates predicted MTSs in 1,004 proteins, whereas TargetP identified cleavable presequences in only 656 proteins, corresponding to 60–90% of mitochondrial proteins and highlighting substantial divergence between the algorithms. To probe for potential substrates of the human orthologue of yeast ICP55, we searched for the established MPP-ICP55 cleavage motifs derived from yeast3,6 and plant datasets7,8 (characterized by an MPP recognition site with R or K at position –2, followed by a bulky hydrophobic residue—Y, L or F—removed by Icp55). Using this criterion, we identified 184 (MitoFates, which directly predicts Icp55 substrates) and 166 (TargetP) putative ICP55 substrates in human mitochondria (Extended Data Fig. 1b,c). Motif visualization based on relative amino-acid frequencies at the predicted cleavage sites revealed a clear enrichment...

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Selective ribosome profiling reveals that nearly 20% of mitochondrial proteins in human cells are imported during translation on cytosolic ribosomes. Cotranslational import requires an N-terminal presequence but is delayed until a large domain emerges and prioritizes large multi-domain proteins. This multi-layered sorting mechanism enables cells to balance the import demands for the mitochondrial proteome with diverse biophysical properties.

Hsu et al. show that mitochondrial import blockage stress activates the ATP-dependent protease YME1L1, which degrades mitochondrial presequence translocase TIM23 subunits to promote cell growth.

Hsu et al. show that mitochondrial import blockage stress activates the ATP-dependent protease YME1L1, which degrades mitochondrial presequence translocase TIM23 subunits to promote cell growth.

Hsu et al. show that mitochondrial import blockage stress activates the ATP-dependent protease YME1L1, which degrades mitochondrial presequence translocase TIM23 subunits to promote cell growth.

Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs ...

Mitochondrial biogenesis relies on hundreds of proteins which are derived from genes encoded in the

Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs ...

Mitochondrial function relies on the precise targeting and import of cytosolic proteins into mitochondrial subcompartments. Most matrix-targeted proteins follow the presequence pathway, which directs ...

Mitochondrial biogenesis relies on hundreds of proteins which are derived from genes encoded in the

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to si