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© The Rockefeller University Press, 0021-9525/2002/8/647 $5.00
The Journal of Cell Biology, Volume 158, Number 4, August 19, 2002 647-657

The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide–dependent deacetylase

¹ Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, CA 94103
² Applied Tumor Virology, Deutsches Krebsforschungszentrum, D–69120 Heidelberg, Germany
³ VA Medical Center, Pittsburgh, PA 15240

Address correspondence to Eric Verdin, Gladstone Institute of Virology and Immunology, 365 Vermont St., San Francisco, CA 94103. Tel.: (415) 695-3815. Fax: (415) 695-1364. E-mail: everdin{at}gladstone.ucsf.edu

The yeast silent information regulator (Sir)2 protein links cellular metabolism and transcriptional silencing through its nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase activity. We report that mitochondria from mammalian cells contain intrinsic NAD-dependent deacetylase activity. This activity is inhibited by the NAD hydrolysis product nicotinamide, but not by trichostatin A, consistent with a class III deacetylase. We identify this deacetylase as the nuclear-encoded human Sir2 homologue hSIRT3, and show that hSIRT3 is located within the mitochondrial matrix. Mitochondrial import of hSIRT3 is dependent on an NH₂-terminal amphipathic -helix rich in basic residues. hSIRT3 is proteolytically processed in the mitochondrial matrix to a 28-kD product. This processing can be reconstituted in vitro with recombinant mitochondrial matrix processing peptidase (MPP) and is inhibited by mutation of arginines 99 and 100. The unprocessed form of hSIRT3 is enzymatically inactive and becomes fully activated in vitro after cleavage by MPP. These observations demonstrate the existence of a latent class III deacetylase that becomes catalytically activated upon import into the human mitochondria.

Key Words: HDAC; chromatin; 11p15.5; apoptosis; acetylation

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