Mitochondrial oxidative damage and human diseases

A number of human diseases are associated with increased cell death caused by free radicals. These include degenerative diseases such as Parkinson's disease, Friedreich's ataxia and diabetes. Free radicals are reactive by-products of normal metabolism that damage cell components thereby disrupting normal function and leading to cell death. Mitochondria are the major source of free radicals within cells. These free radicals are formed as mitochondria consume the oxygen we breathe to make energy available to the cell. Mitochondria are also central to determining how cells die, consequently free radical damage to mitochondria is an important cause of cell death. We have developed procedures to target novel molecules to mitochondria. The hope is that these new molecules will enable us to elucidate the mechanisms by which free radicals damage mitochondria and increase cell death in human diseases. Some of these molecules are antioxidants that should block the effects of free radicals. Therefore this approach may also lead to novel therapies to decrease mitochondrial oxidative stress in human diseases such as Alzheimer's Disease and Parkinson's Disease.

Mitochondria are central to the function of human cells because they make energy available to the cell in a usable form and because they are central to a number of pathways of cell death. Consequently it is unsurprising that defects in mitochondrial function contribute to a number of human diseases, including neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia. Damage to mitochondria also contributes to the pathophysiology of heart attack, stroke and diabetes. In this project my group are developing new tools to target molecules to mitochondria in order to understand the processes by which mitochondrial damage occurs and to develop ways in which this damage can be prevented or repaired in human diseases. In carrying out this work we seek to understand how mitochondrial damage occurs in yeast, cultured mammalian cells and in rodent models of mitochondrial damage. One of the most important causes of mitochondrial damage is thought to be the formation of free radicals by mitochondria as a byproduct of their normal function. These short lived but reactive species cause damage to mitochondria DNA, proteins and lipids thereby disrupting normal mitochondrial function. A consequence of this damage is that it causes cells to undergo cell death by both apoptotic and necrotic pathways. We are particularly interested in understanding the links between mitochondrial damage and increased cell death. To unravel the role of mitochondrial free radicals in cell death requires a range of techniques from molecular biology, cell biology and biochemistry. In addition to these standard approaches, we are also developing a strategy that is proving to be particularly useful. This is the selective targeting of molecules to mitochondria within cells. To do this we use the large membrane potential across the mitochondrial inner member to drive the uptake of lipophilic cations to which we have attached biologically active molecules. These active molecules include antioxidants and reporter molecules designed to respond to free radicals. By using these molecules we are able to both estimate and block mitochondrial oxidative damage, and thereby infer its role in cell death. In related work we are also developing strategies to direct large molecules such as proteins and nucleic acids to mitochondria in order to repair the damage caused to mitochondria by free radicals. The approaches we are developing may allow us to measure or manipulate mitochondria processes independently of the rest of the cell. This has scientific potential in helping us understand the roles of mitochondria within the cell. As some of the molecules being developed may prevent or repair mitochondrial damage they may lead to improved therapies for human diseases involving mitochondrial dysfunction. These include degenerative diseases such as Parkinson's disease and diabetes and the general pathological changes associated with ageing.