Aleksandra Trifunovic - C 15

Manipulation of CLPP protease to complement mitochondrial respiratory deficiency

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 mitochondrial DNA (mtDNA) or nuclear DNA encoded genes of mitochondrial proteins cause diseases affecting OXPHOS system. The mitochondrial diseases whose prevalence has been estimated to be 1:5000, are very heterogeneous from a clinical, genetical, biochemical and molecular perspective and can affect patients at any age. Moreover, dysfunction of mitochondrial OXPHOS system has emerged as a key factor in a myriad of “common” diseases, including neurodegenerative and metabolic disorders like Parkinson’s and Alzheimer’s Disease, Type 2 Diabetes, and was linked to aging process. Despite all this, it is surprising that our understanding of the mechanisms governing the mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored.
We have recently shown that slowing down the rate of mitochondrial translation by knocking out mitochondrial matrix protease, CLPP could ameliorate mitochondrial cardiomyopathy caused by loss of mitochondrial aspartate tRNA synthase (DARS2). We propose to further explore therapeutic possibilities of CLPP deficiency induced by genetic manipulation or usage of inhibitors in various cell lines derived from patients carrying either mutation in mitochondrial tRNA genes (MT-TRNA) or mitochondrial tRNA synthetase genes (aaRS2), as well as in a mouse model for mitochondrial encephalopathy.

Clinical/medical relevance and sustainability in disease understanding

While the exact numbers of children and adults suffering from mitochondrial disease are hard to determine because of frequent misdiagnosing, we now know that the prevalence of mitochondrial diseases is approaching that of childhood cancers. Our project holds a strong promise of possible therapeutic intervention in a largest group of mitochondrial diseases that directly affect the function of mitochondrial tRNAs, through manipulation of rates of mitochondrial protein synthesis. 


Prof. Dr. rer. nat. Aleksandra Trifunovic

Inst. for Mitochondrial Diseases and Ageing

Prof. Dr. rer. nat. Aleksandra Trifunovic

Work +49 221 478-84291

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

Publications - Aleksandra Trifunovic

Link to PubMed