MITOCHONDRIAL ATP SYNTHASE SUBUNIT-C STORED IN HEREDITARY CEROID-LIPOFUSCINOSIS CONTAINS TRIMETHYL-LYSINE

The subunit c protein of mitochondrial ATP synthase accumulates in lys osomal storage bodies of numerous tissues in human subjects with certa in forms of ceroid-lipofuscinosis, a degenerative hereditary disease. Subunit c appears to constitute a major fraction of the total storage- body protein. Lysosomal accumulation of subunit c has also been report ed in putative animal models (dogs, sheep and mice) for ceroid-lipofus cinosis. In humans with the juvenile form of the disease, hydrolysates of total storage-body protein have been found to contain significant amounts of epsilon-N-trimethyl-lysine (TML). TML is also abundant in s torage-body protein hydrolysates from affected dogs and sheep. These f indings suggested that one or both of the two lysine residues of subun it c might be methylated in the stored form of the protein. The normal subunit c protein from mitochondria does not appear to be methylated. In a putative canine model for human juvenile ceroid-lipofuscinosis, residue 43 of the storage body subunit c was previously found to be TM L. In the present study, subunit c was isolated from the storage bodie s of humans with juvenile ceroid-lipofuscinosis, and from sheep and mi ce with apparently analogous diseases. In all three species, partial a mino acid sequence analysis of the stored subunit c indicated that the protein contained TML at residue 43. These findings strongly suggest that specific methylation of lysine residue 43 of mitochondrial ATP sy nthase plays a central role in the lysosomal storage of this protein.