SIRT4

SIRT4 is a member of the sirtuin family of NAD+-dependent enzymes and is primarily located in the mitochondrial matrix. In humans, it is encoded by the SIRT4 gene and is one of seven mammalian sirtuins (SIRT1–SIRT7). SIRT4 activity links cellular energy status to mitochondrial metabolism.

Biochemical activity: The enzyme is best known for its ADP-ribosyltransferase activity, modifying mitochondrial proteins and thereby regulating metabolism. The most well-established substrate is glutamate dehydrogenase (GDH); ADP-ribosylation of GDH reduces its activity and inhibits glutaminolysis, influencing amino acid utilization and insulin secretion in pancreatic beta cells. SIRT4 also displays weak deacetylase or other demodifying activities in some assays, but ADP-ribosylation is its defining activity in vivo.

Physiological roles: By controlling GDH and related mitochondrial enzymes, SIRT4 regulates energy production, lipid and amino acid metabolism, and the response to nutrient availability. It participates in the regulation of insulin release in response to glucose levels and contributes to cellular responses to metabolic stress and aging.

Clinical relevance: Altered SIRT4 expression or activity has been observed in various cancers and metabolic disorders, with contexts suggesting both tumor-suppressive and pro-survival roles depending on tissue type and condition. Research continues to clarify its potential as a therapeutic target for metabolic diseases and cancer.

Regulation and structure: SIRT4 is a mitochondrial matrix protein that relies on NAD+ for activity, placing it within the network of NAD+-dependent mitochondrial regulators. Its expression and activity respond to nutritional cues and cellular energy status, coordinating with other sirtuins to modulate mitochondrial function.