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Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPR mt
Author(s) -
Seiferling Dominic,
Szczepanowska Karolina,
Becker Christina,
Senft Katharina,
Hermans Steffen,
Maiti Priyanka,
König Tim,
Kukat Alexandra,
Trifunovic Aleksandra
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642077
Subject(s) - caenorhabditis elegans , mitochondrion , unfolded protein response , biology , microbiology and biotechnology , translation (biology) , genetics , gene , messenger rna , endoplasmic reticulum
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 DARS 2‐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 DARS 2 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.