Mitochondria are frequently implicated in several human disease states. From neurological disorders like Alzheimer’s disease and Autism Spectrum Disorder, to metabolic conditions like diabetes and obesity, energy abnormalities are seen in diverse illnesses. In fact, mitochondrial dysfunctions have also been shown to be involved in Parkinson’s disease, Down syndrome, heart failure, and even cancer. What is the relevance of these tiny powerhouses in such diverse, seemingly unrelated conditions?

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Mitochondrial dysfunction appears to be a central theme in a variety of human pathologies. These membranous organelles are responsible for the generation of adenosine triphosphate, or ATP, the major molecule by which cellular energy is transferred and spent. Think of them as the energy factories living in each of your cells, performing the ever-essential task of providing you with the ATP to go about your day. This specialized function is reflective of a complex mitochondrial structure: they contain their own DNA and encode several of their own proteins, which differ from those in the rest of the cell.

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A widely accepted concept is that inhibition of key mitochondrial enzymes decreases ATP production and increases the formation of reactive oxygen species (ROS). ROS are the same series of evil chemical reactions that cause cars to rust, apples to turn brown, and skin to wrinkle. These ROS also damage mitochondrial DNA, components of the electron transport chain, and other important mitochondrial factors. A vicious cycle is thereby triggered: mitochondrial impairment leading to ROS, which cause more mitochondrial damage that creates additional oxidative stress and ROS.

When mitochondria are not working properly, cells cannot produce enough energy, especially when there are plenty of ROS around to tamper with ATP production. In the brain, this wreaks cellular havoc. Neurons have high rates of metabolic activity and need to be ready to respond promptly to activity-dependent events that can trigger high bioenergetic demands. When neurons can’t produce enough energy, they don’t fire properly, connections aren’t formed, and brain function is affected. Brain function in particular is highly dependent on energy, so it’s not surprising that mitochondrial alterations lead to neuronal dysfunction and degeneration seen in diverse neurological conditions.

In fact, this very problem of energy loss is also found in chronic disease. Type 2 diabetes mellitus is associated with reduced mitochondrial activity in insulin-responsive tissues and accelerates progression of organ dysfunction by increased production of ROS. Additionally, the mechanisms of heart failure involve severe mitochondrial dysfunction, which ultimately lead to failure of contractile tissue.

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Mitochondrial dysfunction favors the development of diverse neurological and chronic illnesses. Down Syndrome patients suffer from energy deficits and often find themselves with several comorbid conditions, namely Alzheimer’s Disease, Autism Spectrum, and diabetes. As JL mentioned on her previous post, increasing mitochondrial activity to functional levels did not reverse the symptoms of energy failure, but rather increased ROS and cell damage. These results suggest that the most critical factor in these conditions may be energy failure itself, and not ROS.

Perhaps the answer to neurological and chronic illnesses will not be found in mitochondria alone. But studies that focus on the function and dysfunction of mitochondrial biology provide important steps to tackle disease processes of several conditions all at once.  By determining the causal underlying cellular and molecular processes that lead to energy deficits, novel therapeutic strategies focused around mitochondria can be used to treat diverse disorders.

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Bayeva M., Gheorghiade M. & Ardehali H. (2012). Mitochondria as a Therapeutic Target in Heart Failure, Journal of the American College of Cardiology, DOI: 10.1016/j.jacc.2012.08.1021
Exner N., Lutz A.K., Haass C. & Winklhofer K.F. (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences, The EMBO Journal, 31 (14) 3038-3062. DOI: 10.1038/emboj.2012.170
Helguera P., Seiglie J., Rodriguez J., Hanna M., Helguera G. & Busciglio J. (2013). Adaptive Downregulation of Mitochondrial Function in Down Syndrome, Cell Metabolism, 17 (1) 132-140. DOI: 10.1016/j.cmet.2012.12.005
Szendroedi J., Phielix E. & Roden M. (2011). The role of mitochondria in insulin resistance and type 2 diabetes mellitus, Nature Reviews Endocrinology, 8 (2) 92-103. DOI: 10.1038/nrendo.2011.138
Querfurth H.W. & LaFerla F.M. (2010). Alzheimer’s Disease, New England Journal of Medicine, 362 (4) 329-344. DOI: 10.1056/NEJMra0909142
Images adapted from Corbis (Light bulb, mitochondria), and Schmidt C.W. (2010). Mito-Conundrum: Unraveling Environmental Effects on Mitochondria,Environmental Health Perspectives, 118 (7) a292-a297. DOI: 10.1289/ehp.118-a292

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