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.
The Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA.
Maria
M
Damiano
Anatoly A
AA
Starkov
Susanne
S
Petri
Kathuna
K
Kipiani
Mahmoud
M
Kiaei
Marina
M
Mattiazzi
M
M
Flint Beal
Giovanni
G
Manfredi
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