1. Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt.
- Author
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Seiferling D, Szczepanowska K, Becker C, Senft K, Hermans S, Maiti P, König T, Kukat A, and Trifunovic A
- Subjects
- Animals, Aspartate-tRNA Ligase deficiency, Cardiomyopathies metabolism, Cardiomyopathies pathology, Female, Gene Knockout Techniques, HEK293 Cells, Humans, Male, Mice, Mice, Knockout, Mitochondria, Heart metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Stress, Physiological, Cardiomyopathies genetics, Endopeptidase Clp deficiency, Mitochondria, Heart genetics, Signal Transduction
- Abstract
The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans Far less is known about mammalian UPR(mt) signaling, although similar roles were assumed for central players, including CLPP To better understand the mammalian UPR(mt) signaling, we deleted CLPP in hearts of DARS2-deficient animals that show robust induction of UPR(mt) due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR(mt) 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 UPR(mt) signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases., (© 2016 The Authors.)
- Published
- 2016
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