Mitochondrial membrane permeabilization upon interaction with lysozyme fibrillation products: Role of mitochondrial heterogeneity

Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, although the relative degree of this functional impairment and the mechanism of selective vulnerability in different regions of the brain related to various neurological diseases are not completely understood. In a recent study, we reported on brain mitochondrial membrane permeabilization upon interaction with hen egg white lysozyme (HEWL) protofibrils, and came to the conclusion that mitochondrial heterogeneity could offer an explanation for some of our observations. Accordingly, the first part of the present investigation was devoted on studies involving interaction of HEWL fibrillation products with mitochondria isolated from various areas of the brain, known to be affected in a number of well-characterized neurodegenerative conditions. This was followed by looking at heart and liver mitochondria. Membrane permeabilization was investigated by monitoring release of mitochondrial enzymes. Mitochondria isolated from cortex and hippocampus showed greater sensitivities than those prepared from substantia nigra. Results clearly demonstrate heterogeneity in brain mitochondria together with a higher resistance to permeabilization in these organelles in comparison with those isolated from liver and heart. Calcium and spermine were found to be more effective in preventing permeabilization in brain mitochondria, as compared to liver and heart. The structure–function aspects and physiological significance of the observations in relation to differences in composition, biophysical nature and morphological properties of mitochondria are discussed. It is argued that studies on heterogeneity in cellular membranes, the primary targets of toxic protofibrils, may provide important insights into mechanism of toxicity, with clinical and pathological manifestations.

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► We describe interaction of HEWL fibrillation products with mitochondria.
► Heterogeneity in brain mitochondria was explored.
► Lower permeabilization in brain mitochondria compared to those from liver and heart
► Calcium and spermine inhibited mitochondrial membrane permeabilization.
► Membrane heterogeneity may play an important role in protofibril cytotoxicity.