The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans. Far less is known about mammalian UPRmt signaling, although similar roles were assumed for central players, including CLPP. To better understand the mammalian UPRmt signaling, we deleted CLPP in hearts of DARS2‐deficient animals that show robust induction of UPRmt due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPRmt in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPRmt signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.
Loss of mammalian ClpP does not affect the mitochondrial unfolded protein response (UPRmt) under proteotoxic stress. Instead, loss of ClpP alleviates mitochondrial cardiomyopathy by partially rescuing the mitochondrial translation defect and reducing the level of potentially toxic peptides.
Loss of ClpP alleviates progressive mitochondrial cardiomyopathy.
ClpP is not required for mammalian UPRmt signaling.
Loss of ClpP slows down mitochondrial translation, thereby increasing the level of functional OXPHOS complexes in DARS2‐deficient mice.
EMBO Reports (2016) 17: 953–964
- Received January 21, 2016.
- Revision received March 22, 2016.
- Accepted April 12, 2016.
- © 2016 The Authors