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.