Mechanisms for regulation of brain mitochondria by extramitochondrial Ca2+ as new targets of neurodegeneration

Due to complex interactions between mitochondria and other cell compartments there are diverse possibilities for involvement of mitochondria in the pathophysiology of neurodegeneration (1). Recently we detected for the first time at isolated muscle mitochondria of R6/2 mice an increased sensitivity of OXPHOS against Ca²⁺-stress (2). Therefore we systematically investigated the role of cytosolic Ca²⁺ (Ca²⁺ _cyt) for the regulation of OXPHOS at isolated brain mitochondia of normal and transgenic animals as models of the neurodegenerative diseases Huntington, Parkinson and Alzheimer.

In contrast to the textbooks we found that Ca²⁺ _cyt fully regulates the active respiration of brain mitochondria using the substrates glutamate/malate and also a-glycerophosphate on demand on the actual energy requirements. This occurs via the Ca²⁺ _cyt-stimulation of the glutamate aspartate carrier (aralar) and the mitochondrial a-glycerophosphate dehydrogenase. Both enzymes have regulatory Ca²⁺ binding sites on the mitochondrial surface (in the intermembrane space) and are main constituents of the malat-aspartat-shuttle and the a-glycerophosphate-shuttle, respectively. Activity of both shuttles is reversibly and effectively regulated by Ca²⁺ _cyt in the range of physiological Ca²⁺ _cyt-concentrations between 50 and 300 nM Ca²⁺ _cyt. (3–5).

Brain mitochondria of transgenic animals were investigated with specific respirometric protocols (6). Active glutamate respiration of brain mitochondria from different transgenic Huntington animals was lower and inhibition by Ca²⁺-overload started at lower Ca²⁺ _cyt compared to the controls. Similar results were obtained with transgenic a-synuclein mice (Parkinson) and also at preliminary measurements of Alzheimer mice with Aß42-pathology.

Besides aralar and a-glycerophosphate dehydrogenase there are further proteins (porin, MgATP-carrier, Ca²⁺-uniporter, permeability transition pore) on the mitochondrial surface with assumed or confirmed regulatory Ca²⁺-binding sites. Therefore, we hypothesize that the cytotoxic proteins (Huntingtin_exp, a-Synuclein, Aß42, TauP301L) can interact with these Ca²⁺-binding sites, disturbing the normal interactions between mitochondria and Ca²⁺ _cyt which consequently causes mitochondrial dysfunction, energetic depression mitochondrial cell death and atrophy (1–5).

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