Follow-up study of subunit c of mitochondrial ATP synthase (SCMAS) in Batten disease and in unrelated lysosomal disorders

Abstract

Immunohistochemical and biochemical studies of subunit c of mitochondrial ATP synthase (SCMAS) storage were carried out in neuronal ceroid lipofuscinosis (NCL) and in a series of unrelated inherited and acquired lysosomal disorders. In the NCL group, represented by the late infantile, early juvenile and juvenile types, SCMAS storage was generalized neurovisceral, with considerable difference in the visceral storage pattern between the types. In late infantile NCL the SCMAS storage was intensive and corresponded to the generalized, autofluorescent, uniformly curvilinear material, irrespective of the cell type affected. In both early juvenile and juvenile NCLs the SCMAS storage was strong and almost uniform in brain neurons, but did not correlate entirely with the visceral autofluorescent storage pool, being undetectable in autofluorescent storage deposits in a constant set of tissues. In the adult (Kufs) type, the brain neurons were stained with various intensity. In infantile NCL, SCMAS storage was restricted to some of the persisting neurons. In a series of inherited lysosomal enzymopathies and acquired lysosomal disorders, excessive SCMAS accumulation was found only in secondary neuronal lipopigments. It occurred as an early and more uniform phenomenon in mucopolysaccharidosis types I, II, IIIA and in polysulphatase deficiency, or as a delayed varied phenomenon in protracted variants of mucolipidosis I, Niemann-Pick types A and C, and GM2 and GM1 gangliosidoses. Neuronal ageing led to an irregular increase in immunodetectable SCMAS epitope in some neuronal lipofuscin granules. There was no evidence of significant SCMAS lysosomal accumulation in non-neural cells in the whole group, regardless of whether lipofuscin or ceroid accumulation occurred or not. The neuronal SCMAS storage is thus nosologically a common unspecific phenomenon, which is especially amplified in NCL. The specificity of the NCL storage process is shown by the fact that even lysosomes of non-neuronal cells in NCL accumulate SCMAS.

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

“…An examination of CNS mitochondria did not reveal overt ultrastructural abnormalities in cat F Ϫ/Ϫ mice. A major constituent of lamellar-like inclusions in NCL is mitochondrial ATP synthase subunit c (6). Immunoblotting was performed to determine whether the accumulated lipofuscin granules in cat F-deficient mice contain subunit c. However, no difference in subunit c protein amounts was observed between lysates of 19-month-old cat F WT and cat F Ϫ/Ϫ spinal cords prepared by methods previously shown to extract subunit c from lipofuscin (6) (Fig.…”

Autophagy, organelles and ageing

“…Although non-degradable material can theoretically form in any cellular compartment and then be delivered to lysosomes through autophagy, there are good reasons to believe that lysosomes themselves are the principal sites at which lipofuscin is produced [75]. As a result of autophagy, lysosomes contain a wide variety of subcellular structures, most importantly mitochondria, which are rich in lipidaceous membrane components and iron-containing proteins, such as cytochrome c. The formation of lipofuscin from mitochondrial components is supported by the presence of the ATP synthase subunit c in age pigment granules [76]. In professional scavengers, such as RPE cells and macrophages (foam cells) in atheroma, a large portion of lipofuscin forms from endocytosed (heterophagocytosed) material [77,78].…”

Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B

“…Ubiquitin accumulation has been found in some areas of the brain of mice with MPS VII [10] and MPS III A [11]. An accumulation of subunit c of mitochondrial ATP synthase (SCMAS) was shown by immunohistochemistry to accumulate in the brain of human patients affected by MPS I, II and III A [12].…”