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The infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease. Despite our knowledge that palmitoyl-protein thioesterase-1 (PPT1)-deficiency causes INCL, the molecular mechanism(s) of neurodegeneration and the drastically reduced lifespan of these patients remain poorly understood. Consequently, an effective treatment for this disease is currently unavailable. We previously reported that oxidative stress-mediated abnormality in mitochondria activates caspases-9 pathway of apoptosis in INCL fibroblasts and in neurons of Ppt1-knockout (Ppt1-KO) mice, which mimic INCL. Since mitochondria play critical roles in maintaining cellular energy homeostasis, we hypothesized that oxidative stress-mediated disruption of energy metabolism and homeostasis may contribute to INCL pathogenesis. We report here that, in cultured INCL fibroblasts and in the brain tissues …