Batten disease and mitochondrial pathways of proteolysis.

Most forms of Batten Disease (BD), a group of neurodegenerative diseases, are characterized by the accumulation within lysosomes of the very hydrophobic protein subunit 9 of the mitochondrial F1F0-ATP synthase (F-ATPase). It is now known that the cause of the accumulation of this protein in BD is a reduction in its rate of degradation. Because the F-ATPase subunit 9 accumulates within lysosomes of BD tissues, the degradative defect seemed likely to be within lysosomes. However, a recent report showed that delayed degradation of F-ATPase subunit 9 was evident in fibroblasts from BD patients long before any of the protein could be found within lysosomes. Therefore, the defective degradation pathway in BD appears likely to be intramitochondrial. We review the rather limited information about pathways of degradation of mitochondrial proteins. Mitochondria can be taken up and degraded by lysosomes through a process called macroautophagy. However, substantial proteolysis also occurs within mitochondria. Several different proteases are present within mitochondria, but their normal protein substrates are largely unknown. Like proteases from bacteria, many of these proteases operate in concert with molecular chaperones. We hypothesize that a mutation in a gene encoding a mitochondrial protease or a mitochondrial molecular chaperone leads to impaired degradation of F-ATPase subunit 9 in BD. This proteolipid may then form intracellular aggregates that are eventually sequestered into lysosomes.