Rego AC, Oliveira CR.
Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases.
Neurochem Res. 2003 Oct;28(10):1563-74.
PubMed.
The recent paper by Rego and Oliveira has fully described the role of mitochondrial abnormalities as a key target, not only as ATP producers through oxidative phosphorylation, but also as regulators of intracellular Ca2+ homeostasis and endogenous producers of ROS.
In particular, an increase in the mitochondrial Ca2+ level can physiologically enhance ATP generation by activating matrix dehydrogenase. At the same time, as mentioned by Rego and Oliveira, such an increase can also promote ROS generation. It is well-known that neurons are highly dependent on glucose for ATP generation, which is necessary for many biochemical processes but also produces ROS as byproducts of oxidative phosphorylation within the mitochondria. Oxidative stress followed by neuronal damage inevitably occurs if the amount of ROS produces an imbalance between several antioxidants. The role of oxidative stress in the pathogenesis, particularly of AD, is well-established (Nunomura et al., 2001). In addition, the role of mitochondrial abnormalities as a key target for the development of AD is well-documented (Hirai et al., 2001; Aliev et al., 2002; 2003a2003b; 2003c).
The most relevant hallmarks of the cell death process include apoptosis (Rego and Oliveria, 2003) and other pathways (Aliev et al., 2002; 2003a-c); recent advances in understanding the mechanisms involved also have been made. The role of mitochondria in the regulation of Ca2+ homeostasis and in ROS generation during excitotoxicity and general cell demise is also analyzed. Moreover, recent evidence of involvement of mitochondrial DNA deletions that appear to be a key target for the development of neuronal and other cellular compartments in human AD brain (Aliev et al., 2002; Hirai et al., 2001) as well as transgenic mice (Aliev et al., 2002; 2003a-c) before amyloid deposition suggest mitochondria as a primary target for oxidative stress-induced damage (Nunomura et al., 2001). Rather than supporting an old dogma regarding the neuronal origin of neurodegenerative diseases, this data could open a new window for a better understanding of the pathogenesis of neurodegenerative diseases and for the development of new and more effective therapies in the near future.
References:
Rego AC, Oliveira CR.
Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases.
Neurochem Res. 2003 Oct;28(10):1563-74.
PubMed.
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA.
Mitochondrial abnormalities in Alzheimer's disease.
J Neurosci. 2001 May 1;21(9):3017-23.
PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA.
Oxidative damage is the earliest event in Alzheimer disease.
J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67.
PubMed.
Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL, Vinters HV, Head E, Perry G, Lamanna JC, Friedland RP, Cotman CW.
Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice.
Ann N Y Acad Sci. 2002 Nov;977:45-64.
PubMed.
Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G.
Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice.
Neurol Res. 2003 Sep;25(6):665-74.
PubMed.
Aliev G, Obrenovich ME, Smith MA, Perry G.
Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease.
J Biomed Biotechnol. 2003;2003(3):162-163.
PubMed.
Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G.
Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease.
Neurotox Res. 2003;5(7):491-504.
PubMed.
Comments
University of Atlanta
The recent paper by Rego and Oliveira has fully described the role of mitochondrial abnormalities as a key target, not only as ATP producers through oxidative phosphorylation, but also as regulators of intracellular Ca2+ homeostasis and endogenous producers of ROS.
In particular, an increase in the mitochondrial Ca2+ level can physiologically enhance ATP generation by activating matrix dehydrogenase. At the same time, as mentioned by Rego and Oliveira, such an increase can also promote ROS generation. It is well-known that neurons are highly dependent on glucose for ATP generation, which is necessary for many biochemical processes but also produces ROS as byproducts of oxidative phosphorylation within the mitochondria. Oxidative stress followed by neuronal damage inevitably occurs if the amount of ROS produces an imbalance between several antioxidants. The role of oxidative stress in the pathogenesis, particularly of AD, is well-established (Nunomura et al., 2001). In addition, the role of mitochondrial abnormalities as a key target for the development of AD is well-documented (Hirai et al., 2001; Aliev et al., 2002; 2003a 2003b; 2003c).
The most relevant hallmarks of the cell death process include apoptosis (Rego and Oliveria, 2003) and other pathways (Aliev et al., 2002; 2003a-c); recent advances in understanding the mechanisms involved also have been made. The role of mitochondria in the regulation of Ca2+ homeostasis and in ROS generation during excitotoxicity and general cell demise is also analyzed. Moreover, recent evidence of involvement of mitochondrial DNA deletions that appear to be a key target for the development of neuronal and other cellular compartments in human AD brain (Aliev et al., 2002; Hirai et al., 2001) as well as transgenic mice (Aliev et al., 2002; 2003a-c) before amyloid deposition suggest mitochondria as a primary target for oxidative stress-induced damage (Nunomura et al., 2001). Rather than supporting an old dogma regarding the neuronal origin of neurodegenerative diseases, this data could open a new window for a better understanding of the pathogenesis of neurodegenerative diseases and for the development of new and more effective therapies in the near future.
References:
Rego AC, Oliveira CR. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res. 2003 Oct;28(10):1563-74. PubMed.
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.
Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL, Vinters HV, Head E, Perry G, Lamanna JC, Friedland RP, Cotman CW. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci. 2002 Nov;977:45-64. PubMed.
Aliev G, Seyidova D, Lamb BT, Obrenovich ME, Siedlak SL, Vinters HV, Friedland RP, LaManna JC, Smith MA, Perry G. Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice. Neurol Res. 2003 Sep;25(6):665-74. PubMed.
Aliev G, Obrenovich ME, Smith MA, Perry G. Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease. J Biomed Biotechnol. 2003;2003(3):162-163. PubMed.
Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G. Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease. Neurotox Res. 2003;5(7):491-504. PubMed.
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