Mitochondrial disorders: From cells towards treatment

Koopman, Werner

Willems, Peter Smeitink, Jan

Werner Koopman (left), Peter Willems (center) and Jan Smeitink (right) of the Depts. of Biochemistry (286) and Pediatrics recently presented their views on how, during the last decade, the analysis of monogenic mitochondrial diseases advanced our understanding of the cellular pathophysiology of mitochondrial dysfunction. This paper was published in the Mechanisms of Disease series of the highly prestigious journal New England Journal of Medicine.

To function normally, human cells require energy in the form of ATP. In many cell types, ATP is primarily generated by mitochondria, which are also key players in other important cellular processes, such as adaptive thermogenesis, ion homeostasis, innate immune responses, production of reactive oxygen species, and programmed cell death (apoptosis). Mitochondrial dysfunction is not only observed in monogenic mitochondrial disorders but is also associated with more common pathologic conditions, such as Alzheimer's disease, Parkinson's disease, cancer, cardiac disease, diabetes, epilepsy, Huntington's disease, and obesity. In addition, a progressive decline in the expression of mitochondrial genes is a central feature of normal human aging. It is not entirely clear whether the changes in expression that occur with aging have positive or negative effects on life span. Given the aging of the population in developed societies and the increasing prevalence of conditions such as Alzheimer's disease and diabetes, the investigation of mitochondrial processes and diseases may make a timely contribution to our understanding of the human aging process and its relationship with the above conditions. Other sources of interference in mitochondrial function include the off-target effects of environmental toxins and frequently used drugs, anesthetics, antibiotics, chemotherapeutic agents, and even aspirin (acetylsalicylic acid). Certain drugs may lead more frequently to adverse reactions and side effects in patients with mitochondrial disorders than in healthy persons. The term "mitochondrial medicine" refers to approaches that have been developed to manage mitochondrial dysfunction and, directly or indirectly, its consequences. Here we summarize the insights obtained from analysis of monogenic mitochondrial diseases. We explain how these insights can contribute to the rational design of intervention strategies for mitochondrial dysfunction and present our ongoing research on human mitochondrial complex I deficiency as an example of mitochondrial medicine.

Werner J.H. Koopman, Peter H.G.M. Willems  and Jan A.M. Smeitink.  Monogenic mitochondrial disorders. N. Engl. J. Med. 2012 (in press)

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