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Pharmacological NAD-boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-mutant Fibroblasts

Lookup NU author(s): Dr Rolando Berlinguer Palmini

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Abstract

Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nicotinamide riboside (NR) ameliorates energetic derangement and symptoms in mouse models of mitochondrial disorders. Whether these pharmacological approaches also improve bioenergetics of human cells harbouring mitochondrial defects is unknown. It is also unclear whether the same signaling cascade is prompted by PARP-1 inhibitors and NR supplementation to improve mitochondrial homeostasis. Here, we show that human fibroblasts mutant for Ndufs1 subunit of respiratory Complex I have similar ATP, NAD and mitochondrial content compared to control cells, but show reduced mitochondrial membrane potential. Interestingly, mutant cells also show increased transcript levels of mtDNA but not nDNA respiratory complex subunits, suggesting activation of a compensatory response. At variance with prior work in mice, however, NR supplementation but not PARP-1 inhibition increased intracellular NAD content in Ndufs1 mutant human fibroblasts. Conversely, PARP-1 inhibitors but not NR supplementation increased transcription of TFAM and mtDNA-encoded respiratory complexes constitutively induced in mutant cells. Still, both NR and PARP-1 inhibitors restored mitochondrial membrane potential and increased organelle content, as well as oxidative activity of Ndufs1-deficient fibroblasts. Overall, data provide the first evidence that in human cells harbouring a mitochondrial respiratory defect exposure to NR or PARP-1 inhibitors activate different signaling pathways not invariantly prompted by NAD increases, but equally able to improve energetic derangement.


Publication metadata

Author(s): Felici R, Lapucci A, Cavone L, Pratesi S, Berlinguer-Palmini R, Chiarugi A

Publication type: Article

Publication status: Published

Journal: Molecular Pharmacology

Year: 2015

Print publication date: 18/03/2015

Online publication date: 18/03/2015

Acceptance date: 18/03/2015

ISSN (print): 0026-895X

ISSN (electronic): 1521-0111

Publisher: American Society for Pharacology and Experimental Therapeutics

URL: http://dx.doi.org/10.1124/mol.114.097204

DOI: 10.1124/mol.114.097204


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