The Current issue of “The view from here” discusses mitochondrial disorders.

The topic of this month’s newsletter from Drug Discovery Today is mitochondrial disorders.

Perhaps not generally recognized by the public, mitochondrial disorders represent some of the most severe diseases to affect mankind. It would not be worthwhile to list these disorders here, although the list is very lengthy. For a flavour of the extent of the conditions being produced as a result of mitochondrial defects you could do worse than consult Wikipedia . The three articles highlighted in this month’s Editor’s Choice newsletter focus upon some of the most current studies into the topic. They point out some of the conditions that could potentially be targeted by drugs produced against mitochondrial targets. Such conditions include neurodegeneration, breast cancer, diabetes, glaucoma, Huntington’s disease and inflammation

The free downloads available in this newsletter highlight some of the most recent developments in translational research in drug discovery. I will elaborate on them below.

The first article, by Neville N. Osborne, Claudia Núñez Àlvarez and Susana del Olmo Aguado of the Fundación de Investigación Oftalmológica, Oviedo, Asturias, Spain, entitled “Targeting of mitochondrial dysfunction as in aging and glaucoma”  examines methods of addressing age related reduction in mitochondrial activity. Neurons depend on their mitochondria for optimum function which is gradually impaired during aging because more electrons are converted to reactive oxygen species rather than being converted to ATP. Retinal ganglion cell mitochondria are additionally affected in glaucoma because of reduced oxygen delivery. Thus, targeting neuronal mitochondria to enhance their function as in glaucoma and aspects associated with aging provides potential ways of attenuating degenerating diseases. A substance worthy of mention is rapamycin, which affects regulated in development and DNA damage 1 (REDD1) and is known to enhance mitochondrial function. REDD1 appears to be prominent in retinal ganglion cells. An alternative exciting non-invasive approach is to use red light therapy that enhances mitochondrial function.

The second article, from Werner J. Geldenhuys, Thomas C. Leeper and Richard T. Carroll, entitled: “mitoNEET as novel drug target for mitochondrial dysfunction” of the University of Akron, OH, USA, discusses how the mitochondrial protein mitoNEET, the target of thiazolidine diones, may be a useful target for other diseases, including neurodegeneration, breast cancer, diabetes and inflammation. Mitochondrial dysfunction plays an important part in the pathology of several diseases, including Alzheimer’s disease and Parkinson’s disease. Targeting mitochondrial proteins shows promise in treating and attenuating the neurodegeneration seen in these diseases, especially considering their complex and pleiotropic origins. Recently, the mitochondrial protein mitoNEET [also referred to as CDGSH iron sulfur domain 1 (CISD1)] has emerged as the mitochondrial target of thiazolidinedione drugs such as the antidiabetic pioglitazone. In this review, we evaluate the current understanding regarding how mitoNEET regulates cellular bioenergetics as well as the structural requirements for drug compound association with mitoNEET. With a clear understanding of mitoNEET function, it might be possible to develop therapeutic agents useful in several different diseases including neurodegeneration, breast cancer, diabetes and inflammation.

Finally, is the review from P. Hemachandra Reddy of Neurogenetics Laboratory, Oregon Health & Science University, USA, entitled, “Increased Mitochondrial Fission and Neuronal Dysfunction in Huntington's Disease: Implications for Molecular Inhibitors of Excessive Mitochondrial Fission”.  The authors discuss how restoring an appropriate level of mitochondrial fission might help in disease, in particular Huntington's Disease. Huntington’s disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.

Steve Carney was born in Liverpool, England and studied Biochemistry at Liverpool University, obtaining a BSc.(Hons) and then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University, in the Departments of Medical Biochemistry and Histopathology. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London, where he worked with Professor Helen Muir FRS and Professor Tim Hardingham, on the biochemistry of experimental Osteoarthritis. He joined Eli Lilly and Co. and held a number of positions in Biology R&D, initially in the Connective Tissue Department, but latterly in the Neuroscience Department. He left Lilly to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. Currently, he also holds an honorary lectureship in Drug Discovery at the University of Surrey, UK. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.

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