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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.

SUBMITTER: Harkcom WT 

PROVIDER: S-EPMC4066477 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents.

Harkcom William T WT   Ghosh Ananda K AK   Sung Matthew S MS   Matov Alexandre A   Brown Kevin D KD   Giannakakou Paraskevi P   Jaffrey Samie R SR  

Proceedings of the National Academy of Sciences of the United States of America 20140602 24

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 disasse  ...[more]