Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology

Abstract

Mitochondrial dysfunctions contribute to neurodegeneration, the locations of which vary among neurodegenerative diseases. To begin to understand what mechanisms may underlie higher vulnerability of the spinal cord motor neurons in amyotrophic lateral sclerosis, compared with brain mitochondria, we studied three major functions of rat brain mitochondria (BM) and spinal cord mitochondria (SCM) mitochondria: oxidative phosphorylation, Ca 2ϩ sequestration, and production of reactive oxygen species (ROS), using a new metabolic paradigm (Panov et al., J. Biol. Chem. 284: 14448 -14456, 2009). We present data that SCM share some unique metabolic properties of the BM. However, SCM also have several distinctions from the BM: 1) With the exception of succinate, SCM show significantly lower rates of respiration with all substrates studied; 2) immunoblotting analysis showed that this may be due to 30 -40% lower contents of respiratory enzymes and porin; 3) compared with BM, SCM sequestered 40 -50% less Ca 2ϩ , and the total tissue calcium content was 8 times higher in the spinal cord; 4) normalization for mitochondria from 1 g of tissue showed that BM can sequester several times more Ca 2ϩ than was available in the brain tissue, whereas SCM had the capacity to sequester only 10 -20% of the total tissue Ca 2ϩ ; and 5) with succinate and succinate-containing substrate mixtures, SCM showed significantly higher state 4 respiration than BM and generated more ROS associated with the reverse electron transport. We conclude that SCM have an intrinsically higher risk of oxidative damage and overload with calcium than BM, and thus spinal cord may be more vulnerable under some pathologic conditions. (250) oxidative phosphorylation; permeability transition; reactive oxygen species MITOCHONDRIAL DYSFUNCTIONS play important roles in pathogenesis of degenerative diseases of the central nervous system (4,14). Although many neurodegenerative diseases are systemic, such as Huntington's disease (15), amyotrophic lateral sclerosis (ALS) (2), and Friedrich's ataxia (8), neurodegeneration predominantly occurs at specific locations within the central nervous system in each of these diseases. An important question in neurodegenerative diseases is what determines localization of neuronal death? There is evidence that, during systemic intoxication with rotenone, or in transgenic mice bearing mutated human G93A SOD1 gene, the pathological changes occur in brain and spinal cord mitochondria, but not in liver mitochondria (10, 32). It was also shown that various brain regions differ in their sensitivity to the deleterious effects of oxygen deprivation (22, 41). Thus, differences in the tissue-specific and regional properties of mitochondria may contribute to selectivity of neurodegeneration.Regarding ALS, one of the major questions is, "Why are motor neurons in the spinal cord more vulnerable than neurons in brain?" Because mitochondrial dysfunctions play important roles in pathogenesis of ALS (2, 24), the above question can be restated as, "What featu...

Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS

“…Nevertheless, our comparative studies of metabolic properties of BM and SCM suggest that potentially the loss of morbidity could be explained by different patterns of substrates metabolism and associated ROS generation in BM and SCM studied in 2007 and 2010. In 2008 we found that BM and SCM isolated from the wild type Sprague Dawley rats began to show metabolic features that were different from those described earlier for the same strain of the wild type and tgSOD1 rats (Panov et al, 2009(Panov et al, , 2011a. In this work we present a comparison of metabolic phenotypes and the substrate-dependent ROS generation in the wild type and transgenic rats with mutant G93A Cu/Zn-superoxide dismutase gene isolated in 2007 and 2010.…”

“…The familial cases with mutations in the SOD1 gene have basically the same mechanism of motor neuron death, but, because mutated SOD1 protein is exceptionally sensitive to oxidative damage, the loss of Cu and Zn may occur at relatively low levels of H 2 O 2 formation by neuronal mitochondria. The predominant involvement of spinal cord can be accounted for by metabolic and structural features of spinal cord and SCM, which were published elsewhere (Panov et al, 2011a(Panov et al, , 2011b.…”

“…However, the etiology and pathogenesis of the disease remain poorly understood. Clinical and experimental evidence showed that ALS is a systemic disease, with particular vulnerability of motor neurons due to some unique properties (Martin et al, 2007;von Lewinski & Keller, 2005;Panov et al, 2011a). Many ALS patients are hypermetabolic, an early and persistent phenomenon (Bouteloup et al, 2009, Desport et al, 2005.…”

“…A comparison of the rates of ROS production by skeletal muscle mitochondria (SMM) (Figure 1 in Muller et al, 2007) and brain (BM) and spinal cord mitochondria (SCM) (see Fig. 7 in Panov et al, 2011a) shows that BM and SCM generate several times more ROS than SMM. Therefore, it is more likely that the causes of degeneration of motor neurons in ALS are associated with primary pathological processes in neurons rather than in muscle.…”

Mutant Cu/Zn-Superoxide Dismutase Induced Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

“…Mitochondria isolated from the neural tissue (brain, spinal cord) have distinct metabolic properties regarding the extent of ROS produced upon oxidation of respiratory substrates (Panov et al, 2011). Especially in G93A-SOD1 transgenic rats, brain and spinal cord mitochondria generate 5-7 fold more ROS than mitochondria of corresponding wild-type tissues.…”