Author's View: a nuclear transcription factor relocalizing to mitochondria rescues cells from proteotoxic aggregates

Abstract

Mitochondrial proteostasis is essential for survival, and imbalances can result in severe human diseases. We identified a novel stress response triggered upon accumulation of proteotoxic aggregates in the mitochondrial matrix. Mitochondria-to-nucleus signaling results in a transcriptional response and translocation of a nuclear transcription factor into mitochondria to maintain mitochondrial gene expression.

Keywords: Mitochondria-to-nucleus communication; dual targeting; mitochondrial proteostasis; mitochondrial unfolded protein response; protein biogenesis.

Figure 1.

Relocalization of the nuclear transcription factor Rox1 protects cells from proteotoxic aggregates in the mitochondrial matrix. Dysfunction of the mitochondrial presequence protease MPP results in accumulation of unprocessed precursor proteins in the matrix that rapidly aggregate. This proteotoxic stress triggers mitochondria-to-nucleus signaling that results in a nuclear transcriptional response and also translocation of the nuclear transcription factor Rox1 into mitochondria. Rox1 binds to mitochondrial DNA (mtDNA) and maintains expression of the mitochondrial genome. This is pivotal for a functional respiratory chain, which generates a stable membrane potential (Δψ) critically to maintain protein import and decreases formation of reactive oxygen species (ROS), which would result in decreased cytosolic translation.