title: NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents.
abstract: Nicotinamide adenine dinucleotide (NAD(+)) is an endogenous enzyme cofactor and cosubstrate that has effects on diverse cellular and physiologic processes, including reactive oxygen species generation, mitochondrial function, apoptosis, and axonal degeneration. A major goal is to identify the NAD(+)-regulated cellular pathways that may mediate these effects. Here we show that the dynamic assembly and disassembly of microtubules is markedly altered by NAD(+). Furthermore, we show that the disassembly of microtubule polymers elicited by microtubule depolymerizing agents is blocked by increasing intracellular NAD(+) levels. We find that these effects of NAD(+) are mediated by the activation of the mitochondrial sirtuin sirtuin-3 (SIRT3). Overexpression of SIRT3 prevents microtubule disassembly and apoptosis elicited by antimicrotubule agents and knockdown of SIRT3 prevents the protective effects of NAD(+) on microtubule polymers. Taken together, these data demonstrate that NAD(+) and SIRT3 regulate microtubule polymerization and the efficacy of antimicrotubule agents.
authors.affiliation: Department of Pharmacology.
authors.forename: William T
authors.initials: WT
authors.lastname: Harkcom
authors.affiliation: Department of Pharmacology.
authors.forename: Ananda K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Department of Medicine, and.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sung
authors.affiliation: Department of Medicine, and.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Matov
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Brown
authors.affiliation: Department of Medicine, and.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.affiliation: Department of Pharmacology, srj2003@med.cornell.edu.
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology; D020552:Comet Assay; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017382:Reactive Oxygen Species; D056566:Sirtuin 3 / Q000502:physiology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D011108:Polymers; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators; D009243:NAD; D014747:Vinblastine; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D015739:Nocodazole; D003078:Colchicine