Overview: Mitochondria: In Health, Disease and Aging

Mechanisms of Mitochondrial Dysfunction in Aging and Neurodegeneration
Compared to other disorders, the development of drugs to treat age-related neurodegenerative diseases is relatively slow. One contributing reason is the difficulty of developing safe treatments that can cross the blood brain barrier. Additionally, and probably most significantly, for most age-related disorders, the mechanism of action that results in neurodegeneration and specific metabolic pathways involved have not been elucidated. These are major obstacles that must be overcome in order to find suitable therapeutic targets for the design of appropriate drugs or the development of preventative therapies.
The research interest of my lab is the interplay between the mitochondria and the intermediary metabolism. We concentrating on understanding the mechanisms of mitochondrial dysfunction in aging and age related disorders. We are interested in specific biochemical pathways that we deduce their relevance to a certain disease finding the common metabolic denominator among the key and established cytopathyologies pertain to that disease. We also work on nutritional and environmental factors that can impact the mitochondria. The research in my lab has yielded several models suggesting new avenues of investigation in three areas:

Mitochondrial Dysfunction and Neurodegeneration
Excessive levels of amyloid-b (Ab) peptide production in Alzheimer’s disease (AD) brain are neurotoxic; however, the molecular mechanism by which Ab triggers mitochondrial and synaptic dysfunction, hypometabolism, and oxidative stress in neurons in AD is not known. We are concentrating on understanding the cell biochemistry of Ab, Ab-precursor protein (AbPP), and the mitochondrion in order to understand the mechanisms underlying neurodegeneration in AD.

Using quantitative and qualitative analysis, my research has identified the dynamics among the key components of the biochemical network-- including Ab, heme, iron homeostasis, and mitochondria-- that contribute to this neurodegeneration. My findings resulted in the construction of a new model that explains how abnormal molecular interactions among these four components, lead to AD. In this model, Ab binds with heme (particularly regulatory heme) to form an Ab-heme complex, which we found to be an enzyme that catalyzes an oxidation–reduction reactions. This Ab-heme enzyme is novel and previously unrecognized.

More research is needed on the interactions of Ab with key metabolites of the mitochondria before designing therapies targeted at these interactions. The current research in my lab may lead to new strategies to prevent or delay AD such as by inhibiting the Ab-heme peroxidase; blocking the formation of Ab-heme to counteract heme deficiency; or using Ab-heme for immunotherapy (targeted at extracellular Ab-heme). The level of Ab-heme in blood of CSF may also serve as a biomarker for AD.

Protecting the Mitochondria During Aging
Mitochondria play an important role in aging and in neurodegenerative diseases and are major the source of free radicals. These free radicals cause oxidative damage to macromolecules, in turn altering the mitochondrial and the cellular biochemistry. A promising therapeutic strategy to prevent oxidative damage is to block the production of free radicals rather than intercept them post-formation. This is one of the goals of the research on mitochondria my laboratory.
A large number of studies demonstrated that a-phenyl-N-tert-butyl nitrone (PBN), a spin trap antioxidant, delays aging in vivo and in vitro. PBN is unique in that no other antioxidants or spin traps mimic its action, thus its mechanism of action was not clear. I studied PBN and identified its unique mechanism of action. I found that the hydrolysis product of PBN, NtBHA, in the anti-aging agent that protect the mitochondria in vivo and in vitro in an efficiency that exceeded PBN. Follow up research in this direction in my lab has identified an additional class of anti-aging agents (the MBs) that protect mitochondria in vivo and in vitro at efficiency that exceeded NtBHA by 1000 folds. This new class of anti-aging agents reversed the decline in cognitive performance and muscle strength in old mice. We are investigating the mechanism of action of these agents. Based on the experimental results, I believe that these agents participate in oxidation-reduction reactions at the level of the mitochondrial electron transport chain (e.g. complex I & IV). This interaction prevents the formation of superoxide radicals, protects the mitochondria from oxidative damage, and promotes mitochondrial biogenesis.

Our eventual goal is to use these agents to prevent the production of free radicals and the mitochondrial dysfunction associated with age-related disabilities. We also actively searching for nutriceutical that may mimic the action of these drugs. 

Mitochondria, Micronutrients Deficiencies, and Environmental Exposure
We also investigating the effects of deficiencies of a group of eight micronutrients, which are essential for heme synthesis, on mitochondrial biochemistry and function. Deficiencies for these micronutrients are common among children, elderly, and in pregnancy. My laboratory was the first to establish a molecular link between the vitamin biotin, heme, and the biochemical integrity of the mitochondria. This work is important for understanding the known teratogenic effects of marginal biotin deficiency as well as the effects of micronutrient deficiencies on mitochondrial function. Micronutrients deficiencies and exposure to environmental factors are known to interfere with heme synthesis, especially the production of regulatory heme. 

The research is aimed at promoting primary methods for prevention and treatment of illnesses by providing better understanding for the role of nutritional and toxicological factors in cellular metabolism.

Selected References:
Atamna, H. (2006) Heme binding to Amyloid-beta peptide: Mechanistic role in Alzheimer's disease. J Alzheimers Dis, 10, 255-266.

Atamna, H. and Boyle, K. (2006) Amyloid-beta peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer's disease. Proc Natl Acad Sci U S A, 103, 3381-3386.

Atamna, H., Newberry, J., Erlitzki, R., Schultz, C.S. and Ames, B.N. (2007) Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. J Nutr, 137, 25-30.

Atamna, H., Paler-Martinez, A. and Ames, B.N. (2000) N-t-butyl hydroxylamine, a hydrolysis product of alpha-phenyl-N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts. J Biol Chem, 275, 6741-6748.