ARH3 catalyzes degradation of mitochondrial matrixaccumulated Poly (ADP‐ribose)

Abstract

Poly (ADP‐ribose) (PAR) metabolism, which is mainly mediated by members of the Poly (ADP‐ribose) polymerase (PARP) and Poly (ADP‐ribose) glycohydrolase (PARG) families, is involved in several cellular pathways including DNA stability, apoptosis, and mitosis. PARG, initially identified as a PAR degrading‐enzyme, exists as multiple isoforms with different subcellular localization, resulting from alternative splicing of the single gene. ADP‐ribosylhydrolase 3 (ARH3) also has PAR‐degrading activity. The enzymes participating in a putative PAR metabolism in mitochondria are still unknown.An alternatively spliced, small human PARG isoform (PARG55) and ARH3 are located in mitochondria owing to a mitochondrial targeting sequence at their N‐terminus. Using a modified PARP1 construct to produce PAR selectively in mitochondria, ARH3‐deficient cells were shown to have more mitochondrial PAR accumulation than wild‐type cells. Overexpression of ARH3 decreased mitochondrial PAR content, while overexpression of PARG55 had no effect. PARG55 was shown to lack exon5, which is essential for PAR‐degrading activity. These data suggest that ARH3 rather than PARG55 is the primary enzyme involved in catalyzing the degradation of PAR in mitochondria.