Universität zu Köln

Rumyantseva, Anastasia ORCID: 0000-0002-7847-6178, Popovic, Milica and Trifunovic, IThAleksandra (2022). CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis. Brain, 145 (1). S. 92 - 105. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

Full text not available from this repository.

Abstract

Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. Therefore, it is not surprising that mutations in either mtDNA or nuclear DNA-encoded genes of mitochondrial proteins cause diseases affecting the oxidative phosphorylation system, which are heterogeneous from a clinical, genetic, biochemical and molecular perspective and can affect patients at any age. Despite all this, it is surprising that our understanding of the mechanisms governing mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored. We recently showed that loss of the mitochondrial matrix protease caseinolytic protease proteolytic subunit (CLPP) ameliorates phenotypes in cells characterized by defects in oxidative phosphorylation maintenance. Here, we build upon this finding by showing that CLPP depletion is indeed beneficial in vivo for various types of neuronal populations, including Purkinje cells in the cerebellum and cortical and hippocampal neurons in the forebrain, as it strongly improves distinct phenotypes of mitochondria encephalopathy, driven by the deficiency of the mitochondrial aspartyl tRNA synthase DARS2. In the absence of CLPP, neurodegeneration of DARS2-deficient neurons is delayed as they present milder oxidative phosphorylation dysfunction. This in turn leads to a decreased neuroinflammatory response and significantly improved motor functions in both double-deficient models (Purkinje cell-specific or forebrain neuron-specific Dars2/Clpp double knockout mice). We propose that diminished turnover of respiratory complex I caused by the loss of CLPP is behind the improved phenotype in Dars2/Clpp double knockout animals, even though this intervention might not restore respiratory complex I activity but rather improve mitochondrial cristae morphology or help maintain the NAD(+)/NADH ratio inside mitochondria. These results also open the possibility of targeting CLPP activity in many other mitochondrial encephalopathies characterized by respiratory complex I instability.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rumyantseva, Anastasia UNSPECIFIED orcid.org/0000-0002-7847-6178 UNSPECIFIED Popovic, Milica UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, IThAleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-667167
DOI:	10.1093/brain/awab303
Journal or Publication Title:	Brain
Volume:	145
Number:	1
Page Range:	S. 92 - 105
Date:	2022
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL-CORD INVOLVEMENT; TRANSFER-RNA SYNTHETASE; BRAIN-STEM; LACTATE ELEVATION; STRESS RESPONSES; LEUKOENCEPHALOPATHY; COMPLEX; CORTEX; CONNECTIONS; HIPPOCAMPUS Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66716