KARS2

KARS2, or lysyl-tRNA synthetase 2, mitochondrial, is a human gene that encodes the mitochondrial form of lysyl-tRNA synthetase. This nuclear-encoded enzyme is produced in the cytosol and imported into mitochondria, where it participates in mitochondrial protein synthesis by attaching lysine to its cognate tRNA during translation of mitochondrial-encoded proteins.

Functionally, KARS2 belongs to the aminoacyl-tRNA synthetase family. Its enzymatic activity charges tRNA^Lys with lysine, a critical step for accurate synthesis of mitochondrially encoded polypeptides that are essential components of the oxidative phosphorylation system. The mitochondrial enzyme shares catalytic features with the cytosolic lysyl-tRNA synthetase but is distinguished by a mitochondrial targeting sequence that directs its import into mitochondria.

Localization and structure: The mitochondrial isoform is directed to mitochondria by an N-terminal targeting peptide and is then processed upon import. Structurally, it retains the conserved core found in lysyl-tRNA synthetases and functions within the broader mitochondrial translation apparatus, coordinating with other mitochondrial tRNA synthetases and translation factors.

Genetics and clinical significance: Variants in KARS2 have been reported in humans and are linked with mitochondrial disease phenotypes. Affected individuals may present with neurodevelopmental delay, hypotonia, seizures, and variable brain imaging abnormalities, with some cases exhibiting signs of impaired mitochondrial energy metabolism such as lactic acidosis. The clinical spectrum is heterogeneous, reflecting variable expressivity and tissue-specific impact on mitochondrial translation. Functional studies in patient cells and model systems support a role for KARS2 in maintaining mitochondrial protein synthesis and respiratory chain function.

Evolution and related genes: KARS2 is conserved across many eukaryotes and represents one of the two paralogous lysyl-tRNA synthetases in humans—the mitochondrial KARS2 and the cytosolic KARS. See also KARS (cytosolic lysyl-tRNA synthetase).