Universität zu Köln

Seiferling, Dominic, Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Becker, Christina, Senft, Katharina, Hermans, Steffen, Maiti, Priyanka ORCID: 0000-0003-4207-0341, Koenig, Tim, Kukat, Alexandra and Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517 (2016). Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt. EMBO Rep., 17 (7). S. 953 - 965. HOBOKEN: WILEY-BLACKWELL. ISSN 1469-3178

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Seiferling, Dominic UNSPECIFIED UNSPECIFIED UNSPECIFIED Szczepanowska, Karolina UNSPECIFIED orcid.org/0000-0003-4689-2350 UNSPECIFIED Becker, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Senft, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermans, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Maiti, Priyanka UNSPECIFIED orcid.org/0000-0003-4207-0341 UNSPECIFIED Koenig, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Kukat, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED orcid.org/0000-0002-5472-3517 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271405
DOI:	10.15252/embr.201642077
Journal or Publication Title:	EMBO Rep.
Volume:	17
Number:	7
Page Range:	S. 953 - 965
Date:	2016
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1469-3178
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UNFOLDED PROTEIN RESPONSE; TRANSFER-RNA SYNTHETASE; PERRAULT SYNDROME; HEARING-LOSS; MISFOLDED PROTEINS; STRESS-RESPONSE; MUTATIONS; MTDNA; ACCUMULATION; GENES Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27140