Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology.
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(2+) 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(2+), 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(2+) than was available in the brain tissue, whereas SCM had the capacity to sequester only 10-20% of the total tissue Ca(2+); 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).
Carolinas Neuromuscular/Amyotrophic Lateral Sclerosis Center, Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, North Carolina 28203, USA. alexander.panov55@gmail.com
Alexander V
AV
Panov
Nataliya
N
Kubalik
Natalia
N
Zinchenko
Daisy M
DM
Ridings
David A
DA
Radoff
Richelle
R
Hemendinger
Benjamin R
BR
Brooks
Herbert L
HL
Bonkovsky
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000502:physiology; D005971:Glutamates / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D023421:Models, Animal; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*
D005971:Glutamates; D008293:Malates; D011773:Pyruvates; D017382:Reactive Oxygen Species; D002118:Calcium
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