Disturbances in mitochondrial quality control and mitochondria-lysosome contact underlie the cerebral cortex and heart damage of mucopolysaccharidosis type II mice

Abstract

Mucopolysaccharidosis type II (or Hunter syndrome) is a lysosomal disease caused by mutations in the IDS gene, which encodes the enzyme iduronate 2-sulfatase. MPS II patients present with systemic clinical manifestations and, in the most severe cases, with severe central nervous system abnormalities. Cardiac alterations are also commonly observed. In this study, we evaluated the communication between mitochondria and lysosomes, as well as mitochondrial dynamics and bioenergetics, mitophagy/autophagy, and redox homeostasis in the cerebral cortex and heart of 6-month-old MPS II mice. Our findings showed a reduction in the content of protein TBC1D15 in the cerebral cortex and heart of MPS II mice and an increase in Rab7 in the heart of these animals, suggesting disturbances in the communication between mitochondria and lysosomes. Furthermore, decreased Drp1 levels, indicative of reduced fission, and increased VDAC1 and COX IV, suggesting an increase in mitochondrial mass, were seen in both tissues. Tom20 was also augmented in the cortex. Changes in parkin levels were also verified, indicating disrupted mitophagy. In the field of bioenergetics, we observed reduced activities of citrate synthase and malate dehydrogenase in the cortex, as well as decreased activities of isocitrate dehydrogenase, creatine kinase, and pyruvate kinase, along with diminished mitochondrial respiration in the cardiac tissue of deficient mice. However, a mild increase in lipid peroxidation was seen only in the heart. Our findings suggest that mitochondria-lysosome crosstalk disruption and bioenergetic failure contribute to the pathophysiology of brain and heart alterations in MPS II.

Keywords: Cerebral cortex; Heart; MPS II mice; Mitochondria-lysosome communication; Mitochondrial alterations; Mucopolysaccharidosis type II.