Universität zu Köln

Kimoloi, Sammy (2018). Modulation of the de novo purine nucleotide pathway as a therapeutic strategy in mitochondrial myopathy. Pharmacol. Res., 138. S. 37 - 43. LONDON: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. ISSN 1043-6618

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Abstract

Mitochondrial myopathy (MM) is characterised by muscle weakness, exercise intolerance and various histopathological changes. Recently, a subset of MM has also been associated with aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) in skeletal muscle. This aberrant mTORC1 activation promotes increased de novo nucleotide synthesis, which contributes to abnormal expansion and imbalance of skeletal muscle deoxyribonucleoside triphosphates (dNTP) pools. However, the exact mechanism via which mTORC1-stimulated de novo nucleotide biosynthesis ultimately disturbs muscle dNTP pools remains unclear. In this article, it is proposed that mTORC1-stimulated de novo nucleotide synthesis in skeletal muscle cells with respiratory chain dysfunction promotes an asymmetric increase of purine nucleotides, probably due to NAD+ deficiency. This in turn could disrupt purine nucleotide-dependent allosteric feedback regulatory mechanisms, ultimately leading to dNTP pools aberration. Pharmacological down-modulation of aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) activity is also proposed as a potential therapeutic strategy in MM exhibiting mTORC1-driven abnormal metabolic reprogramming, including aberrant dNTPs pools.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kimoloi, Sammy UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-164277
DOI:	10.1016/j.phrs.2018.09.027
Journal or Publication Title:	Pharmacol. Res.
Volume:	138
Page Range:	S. 37 - 43
Date:	2018
Publisher:	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Place of Publication:	LONDON
ISSN:	1043-6618
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RIBONUCLEOTIDE REDUCTASE GENE; ACTIVATED PROTEIN-KINASE; PYRIMIDINE BIOSYNTHESIS; AMPK ACTIVATION; DNTP POOLS; METABOLISM; MTOR; INHIBITOR; P53; DEOXYRIBONUCLEOTIDE Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16427