Séminaire de Damien Arnoult, directeur de recherche au CNRS à l’hôpital Paul Brousse à Paris

The February 4, 2021

Jeudi 4 février 2021 11h.

Parkin-independent mitophagy and mitochondrion-mediated Integrated Stress Response

Mitochondrial protein rerouting serves as an evolutionary conserved danger signal to initiate quality control of this organelle. We have observed that the Nod-like receptor (NLR) protein NLRX1 relocated from the mitochondrial matrix to the cytosol following mitochondrial depolarization, where it triggered mitophagy by interacting with the endoplasmic reticulum (ER) protein RRBP1 as a prerequisite for the recruitment of the autophagy protein LC3. Importantly, the NLRX1/RRBP1 pathway was also crucial for mitophagy induced by mitochondrial protein import stress (MPIS), which occurred without the involvement of PINK1. We further identify stimulation with high glucose as a physiological trigger of NLRX1/RRBP1-dependent mitophagy induced through MPIS, suggesting a link between this mitophagy pathway and energetic metabolism. In support, NLRX1 was essential for the endurance capacity of mice undergoing moderate treadmill or voluntary wheel running exercise, and NLRX1-deficient mice displayed blunted exercise- induced gastrocnemius muscle mitophagy. Thus, the NLRX1/RRBP1 pathway functionally connects mitochondrial fitness to the ER to regulate mitophagy induced not only by depolarization but also by MPIS and physiological cues. These results further suggest that MPIS might represent a general trigger for physiological mitophagy. 

The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) by one of the four eIF2a kinases that sense specific cellular stressors. The heme-regulated inhibitor (HRI) is one of these kinases. Recent studies have identified new functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, we have recently reported that HRI-mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and it was described that this eIF2a kinase also serves as a relay for mitonuclear communication after a mitochondrial stress."