Mitochondria send SOS signals when under stress

The cytosol as a sensor of mitochondrial stress

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Mitochondria are vital cellular organelles responsible for energy production through oxidative phosphorylation. However, during cellular stress, mitochondria may accumulate misfolded or damaged proteins, leading to proteotoxicity and impairing their proper function. The UPRmt is an essential cellular defense mechanism that aims to restore proteostasis in mitochondria.

Despite its significance, the precise signaling pathway from mitochondria to the nucleus during UPRmt activation remains an enigma. This study seeks to unravel the molecular mechanisms involved in the communication between mitochondria and the nucleus when mitochondria encounter stress, leading to the initiation of the UPRmt.

The study investigated at Goethe University Frankfurt how cells protect and repair their mitochondria, which are essential for cell function. The researchers found that when mitochondria experience stress, two signals are released in the cell’s cytosol (the fluid inside the cell). These signals are mitochondrial reactive oxygen species (mtROS) and accumulated mitochondrial protein precursors (c-mtProt). Both signals work together to activate a response called the mitochondrial unfolded protein response (UPRmt), which helps fix the damaged mitochondria.

The researchers discovered that mtROS in the cytosol causes specific proteins to change, and this, in turn, leads to the accumulation of c-mtProt. The combination of these signals activates a series of events that trigger the UPRmt, ultimately helping maintain the mitochondria’s health. This study provides valuable insights into how cells deal with stress-related issues in their mitochondria and how this process is regulated at the molecular level.

The study investigates how cells maintain the balance of proteins within mitochondria, the energy-producing organelles, under stressful conditions. During proteotoxic stress, mitochondria activate the mitochondrial unfolded protein response (UPRmt). This nuclear transcriptional response induces specific chaperones and proteases to restore mitochondrial protein balance.

The researchers aimed to understand the communication between mitochondria and the nucleus during UPRmt activation in human cells. They found that two signals, mitochondrial reactive oxygen species (mtROS) and accumulated mitochondrial protein precursors (c-mtProt), work together to initiate the UPRmt. While mtROS oxidizes a cytosolic protein, triggering the recruitment of chaperones to c-mtProt, the accumulation of c-m.

tProt signals UPRmt activation. Additionally, they discovered that ROS are crucial for UPRmt activation, as antioxidants inhibited UPRmt induction while increasing mtROS levels enhanced it. This research highlights the essential role of mtROS in signaling UPRmt. It deepens our understanding of how cells cope with mitochondrial stress.

The study focuses on how cells maintain the balance of proteins within mitochondria, the energy-producing organelles, during stressful conditions. They found that the Unfolded Protein Response in the mitochondria (UPRmt) is triggered by two signals: mitochondrial reactive oxygen species (mtROS) and accumulated mitochondrial protein precursors (c-mtProt) in the cytosol. These signals work together to activate a surveillance mechanism involving specific proteins (DNAJA1 and HSF1), which convey the stress information from mitochondria to the nucleus.

Communication leads to the activation of genes responsible for restoring proteostasis in mitochondria. The researchers confirmed that this mechanism is essential for coping with mitochondrial stress and maintaining cell viability. The study highlights a new understanding of how cells respond to mitochondrial stress, providing potential insights into addressing mitochondrial-related diseases.

Journal Reference:

  1. Sutandy, F.X.R., Gößner, I., Tascher, G. et al. A cytosolic surveillance mechanism activates the mitochondrial UPR. Nature. DOI:10.1038/s41586-023-06142-0.
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