Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt

Dominic Seiferling, Karolina Szczepanowska, Christina Becker, Katharina Senft, Steffen Hermans, Priyanka Maiti, Tim König, Alexandra Kukat, Aleksandra Trifunovic

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)953-964
Number of pages12
JournalEMBO Reports
Issue number7
StatePublished - Jul 1 2016
Externally publishedYes


  • cardiomyopathy
  • CLPP
  • DARS2
  • mitochondrial translation
  • mitochondrial unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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