Dysfunctional mitochondria trap proteins in the intermembrane space, 2025, Tamara Flohr et al

[Mij]

Abstract​

The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood.

Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as “mitochondrial triage of precursor proteins” (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome.

Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
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[Mij]

Poorly energized mitochondria trap a subpopulation of mitochondrial precursor proteins in the intermembrane space. This article introduces ‘mitochondrial triage of precursor proteins’ (MitoTraP) as a mechanism that prevents the mistargeting of non-imported proteins to the nucleus and reduces proteotoxic effects.
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Dysfunctional mitochondria can trap import intermediates in the intermembrane space (IMS).
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Mitoribosomal proteins are enriched among the IMS-trapped proteins.
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The trapping does not require ATP and the mitochondrial import motor.
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Trapping of mitochondrial ribosomal proteins prevents their mistargeting to the nucleus.