NEW INSIGHT INTO LYSOSOMAL PROTEIN STORAGE DISEASE - DELAYED CATABOLISM OF ATP SYNTHASE SUBUNIT-C IN BATTEN-DISEASE

Subunit c is normally present as an inner mitochondrial membrane compo nent of the Fo sector of the ATP synthase complex, but in the late inf antile form of neuronal ceroid lipofuscinosis (NCL) it was also found in lysosomes in high concentrations. Mechanism for specific accumulati on of subunit c in lysosomes is not known. The rate of degradation of subunit c as measured by pulse-chase and immunoprecipitation showed a marked delay of degradation in patients fibroblasts with late infantil e form of NCL. There were no significant differences between control c ells and cells with disease in the degradation of cytochrome oxidase s ubunit IV, an inner membrane protein of mitochondria. Measurement of l abeled subunit c in mitochondrial and lysosomal fractions showed that the accumulation of labeled subunit c in the mitochondrial fraction ca n be detected before lysosomal appearance of radioactive subunit c, su ggesting that subunit c accumulated as a consequence of abnormal catab olism in the mitochondrion and is transferred to lysosomes, through an autophagic process. There were no large differences of various lysoso mal protease activities between control and patient cells. In patient cells sucrose loading caused a marked shift of lysosomal density, but did not a shift of subunit c containing storage body. The biosynthetic rate of subunit c and mRNA levels for P1 and P2 genes that code for i t were almost the same in both control and patient cells. These findin gs suggest that a specific failure in the degradation of subunit c aft er its normal inclusion in mitochondria and its consequent accumulatio n in lysosomes.