Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice.
Mitochondrial respiratory chain dysfunction, impaired intracellular Ca2+ homeostasis and activation of the mitochondrial apoptotic pathway are pathological hallmarks in animal and cellular models of familial amyotrophic lateral sclerosis associated with Cu/Zn-superoxide dismutase mutations. Although intracellular Ca2+ homeostasis is thought to be intimately associated with mitochondrial functions, the temporal and causal correlation between mitochondrial Ca2+ uptake dysfunction and motor neuron death in familial amyotrophic lateral sclerosis remains to be established. We investigated mitochondrial Ca2+ handling in isolated brain, spinal cord and liver of mutant Cu/Zn-superoxide dismutase transgenic mice at different disease stages. In G93A mutant transgenic mice, we found a significant decrease in mitochondrial Ca2+ loading capacity in brain and spinal cord, as compared with age-matched controls, very early on in the course of the disease, long before the onset of motor weakness and massive neuronal death. Ca2+ loading capacity was not significantly changed in liver G93A mitochondria. We also confirmed Ca2+ capacity impairment in spinal cord mitochondria from a different line of mice expressing G85R mutant Cu/Zn-superoxide dismutase. In excitable cells, such as motor neurons, mitochondria play an important role in handling rapid cytosolic Ca2+ transients. Thus, mitochondrial dysfunction and Ca2+-mediated excitotoxicity are likely to be interconnected mechanisms that contribute to neuronal degeneration in familial amyotrophic lateral sclerosis.
Damiano
Maria
M
The Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA.
Starkov
Anatoly A
AA
Petri
Susanne
S
Kipiani
Kathuna
K
Kiaei
Mahmoud
M
Mattiazzi
Marina
M
Flint Beal
M
M
Manfredi
Giovanni
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes; D016472:Motor Neuron Disease / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology*; D010101:Oxygen Consumption / Q000235:genetics; D012119:Respiration / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors
D000255:Adenosine Triphosphate; D045304:Cytochromes c; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002118:Calcium