Alexander Panov, MD, PhD
Senior Scientist, Mitochondrial Biology Group
Carolinas Neuromuscular/ALS Research Laboratory
Department of Neurology
Prior Positions and Experience
||Instructor, Center for Neurodegenerative Diseases, Emory University
||Research Associate, Department of Neurology, School of Medicine, Emory University
||Postdoctoral Associate, Center for Molecular Medicine and Winship Cancer Center, Division of Urology, Emory University
||Research Associate, Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University (Cleveland)
||Postdoctoral Associate, Department of Physiology, School of Medicine, Penn State University (Hershey, Pa.)
||Head of Laboratory, Laboratory of Bioenergetics, Institute of Biochemistry, Academy of Medical Sciences of the USSR (Siberian Branch)
||Head of Laboratory, Laboratory of Medicinal Biochemistry, Institute of Clinical and Experimental Medicine, AMS
||Senior Researcher, Laboratory of Cellular Mechanisms of Adaptation, Institute of Clinical and Experimental Medicine, AMS, 2 Timakova (Novosibirsk, Russia)
||Researcher, Central Research Laboratories, Novosibirsk’s Medical School, 3 Medcadry (Novosibirsk, Russia)
Doctor of Sciences: 1985, The High Certification Commission Under the Ministry Counsel of the USSR
PhD: 1970, Novosibirsk’s State Medical Institute (Novosibirsk, USSR)
MD: 1963, Novosibirsk’s State Medical Institute (Novosibirsk, USSR)
The scientific interests of our laboratory include interactions between various mitochondrial functions, organ and species specific differences in energy metabolism and roles of mitochondrial dysfunction in the neurodegenerative diseases: Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The functions of the central nervous system, which is comprised of the brain and spinal cord, require large amounts of energy. Therefore, it is well established that dysfunctions of mitochondria, the power stations of a cell, play important roles in the pathogenesis of all neurodegenerative diseases, including ALS.
Amyotrophic lateral sclerosis, which is also known as Lou Gehrig’s disease, is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord. The disease is progressive ranging from muscle weakness or stiffness to respiratory dysfunction and ultimately death. Elucidation of the mechanisms underlying the onset and progression of ALS will play a pivotal role in its diagnosis and treatment. Currently I am concentrating on the studies of two problems: 1) differences in structure and function between mitochondria from the brain and spinal cord; 2) metabolic events during neuronal activity, and how they relate to neurodegeneration.
Structural and Functional Differences between Mitochondria from the Brain and Spinal Cord
Superoxide dismutase 1 (SOD1) rats are an animal model of ALS studied in our laboratory. These animals express a mutant form of SOD1 and develop symptoms of ALS in approximately four months. SOD1 is an antioxidant enzyme that is responsible for the neutralization of superoxide radicals. Importantly, studies have shown that in ALS, protein deposits containing mutant SOD1 accumulate in the mitochondria of motor neurons. Using systemic and quantitative approaches in conjunction with the most sensitive and innovative methods, properties of mitochondria from the brain and spinal cord of wild type and SOD1 rats are being compared.
In addition to the development of protein aggregates, other mitochondrial abnormalities have been implicated in the development and progression of ALS. Such abnormalities include respiratory chain defects and increased calcium levels. We have found that spinal cord mitochondria (SCM) have 50 percent lower respiratory activity, and this is associated with diminished quantities of respiratory enzymes. Additionally, spinal cord tissue contains eight times more calcium than brain tissue. The importance of this is that the combined capacity of brain mitochondria to consume and retain calcium exceeded the total brain calcium content by four-fold. Conversely, SCM were capable of consuming only 10% of the total tissue calcium. We have also established that SCM generate significantly more dangerous oxygen radicals than brain mitochondria (Figure 1) (49 KB, PDF) radicals have been implicated in the progression of a host of neurodegenerative diseases. These findings may play an important role in identifying additional mechanisms of motor neuron damage in ALS.
Metabolic Consequences of Neuronal Activity
We are also investigating the roles of mitochondrial metabolism in pathogenesis of ALS. We have evidence that oxidative stress is the most important pathological event in ALS and that it probably occurs at the synapses of motor neurons. We propose that it may be possible to interfere metabolically to enhance energy production and therefore prevent excessive oxidative stress in spinal cord.
In the central nervous system, glutamate is a principle stimulatory neurotransmitter, and neuronal mitochondria play an important role in its metabolism, as well as the inhibitory neurotransmitter GABA. Excessive stimulation of glutamate receptors is associated with neurotoxicity and the generation of reactive oxygen species. Furthermore, during the study of metabolic activities of the brain and spinal cord mitochondria, we have discovered that neuronal mitochondria oxidize a combination of regular substrate pyruvate and glutamate. These observations suggest that mitochondria located at the inter-neuronal junctions, especially in the spinal cord, may be particularly vulnerable to oxidative stress. Clarifying mitochondrial roles in neurodegeneration will be significant in the investigation of drugs that may prevent or suppress excessive oxidative stress in ALS.
Panov A, Schonfeld P, Dikalov S, Hemendinger R, Bonkovsky HL, Brooks BR. The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and ROS generation in postsynaptic brain mitochondria. J Biol Chem. 2009. [PMID: 19304986]
Sherer TB, Richardson JR, Testa CM, Seo BB, Panov AV, Yagi T, Matsuno-Yagi A, Miller GW and Greenamyre JT. Mechanism of toxicity of pesticides acting at complex I: Relevance to environmental etiologies of Parkinson’s disease. J Neurochem 2007; 100: 1469-1479. [PMID: 17241123]
Panov A, Dikalov S, Shalbuyeva N, Hemendinger R, Greenamyre JT and Rosenfeld J. Species- and tissue-specific relationships between mitochondrial permeability transition and generation of ROS in brain and liver mitochondria of rats and mice. Am J Physiol Cell Physiol 2007; 292: C708-C718. [PMID: 17050617]
Panov A, Dikalov S, Shalbueva N, Taylor G, Sherer T and Greenamyre JT. Rotenone model of Parkinson's disease: Multiple brain mitochondria dysfunctions after short-term systemic rotenone intoxication. J Biol Chem 2005; 280: 42026-42035. [PMID: 16243845]
Panov AV, Lund S and Greenamyre JT. Ca2+-induced permeability transition in human Lymphoblastoid cell mitochondria from normal and Huntington's disease individuals. Mol Cell Biochem 2005; 269: 143-152. [PMID: 15786727]
Panov A, Andreeva L and Greenamyre JT. Quantitative evaluation of the effects of mitochondrial permeability transition pore modifiers on accumulation of calcium phosphate: comparison of rat liver and brain mitochondria. Arch Biochem Biophys 2004; 424: 44-52. [PMID: 15019835]