NAD(+) hydrolysis catalyzed by SelO is required for mitochondrial homeostasis
Summary
The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for numerous life processes. However, the mechanisms leading to NAD+ degradation in mitochondria remain insufficiently defined. Through in silico screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn2+ as cofactor. Catalysis depends on SelO's selenocysteine-serine-serine (CSS) C-terminal resi
Content
# NAD(+) hydrolysis catalyzed by SelO is required for mitochondrial homeostasis
*Published: 2026 Apr 30*
The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for
numerous life processes. However, the mechanisms leading to NAD+ degradation in
mitochondria remain insufficiently defined. Through in silico screening of
potential NAD-binding proteins, we discovered a mitochondrial reaction in which
NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO
(SelO), using Mn2+ as cofactor. Catalysis depends on SelO's
selenocysteine-serine-serine (CSS) C-terminal residues, particularly the
selenocysteine 667. In addition to broad metabolic effects, this reaction plays
a pronounced role in lipid utilization via SelO directly associating with fatty
acid oxidation (FAO) enzymes, and it is conserved in both mammalian cells and
bacteria. This reaction is responsive to elevated matrix pH, a signal of
enhanced mitochondrial respiration, and protects mitochondria from sustained
metabolic overactivation. These findings reveal a conserved mechanism for
spatiotemporal NAD+ regulation and highlight its physiological significance in
both prokaryotes and eukaryotes.
DOI: 10.1016/j.cell.2026.01.033