News from the powerhouses

Abstract

The disastrous 2011 Fukushima earthquake and its sequelae have sparked intense public discussions around a set of very fundamental questions such as whether our society should go on to maintain nuclear powerhouses in the future and if yes, which quality control mechanisms would have to be in place to guarantee the highest level of safety, how their efficiency and obedience themselves could reliably be controlled, and finally, at what costs a potential nuclear power phase-out would come. This scenario is quite reminiscent of the situation on the cellular level, where mitochondria, serving the traditional cliche of ‘‘cellular powerhouses’’, work to satisfy the cells’ energy demands by producing ATP through oxidative phosphorylation and glycolysis. This essential organelle function is, however, invariably coupled to the threat of intracellular damage that—when exceeding the capacity of existing molecular control systems—may easily wreak havoc up to killing the cell from within. On the molecular level, the main perpetrators, reactive oxygen species, leak out of the mitochondrial electron transport chain. Once released, this toxic spill then acts by oxidizing membrane lipids and proteins—including, of course, mitochondrial ones—as well as mitochondrial DNA (mtDNA). Importantly, primarily due to its intronand histone-less structure as well as due to insufficient repair mechanisms, the latter is much more susceptible to mutational damage than the genomic DNA of the nucleus. As a result, in addition to occurring at much higher frequencies in comparison to genomic DNA mutations, mtDNA mutations also accumulate in postmitotic cells such as neurons in an agedependent manner, as reflected clinically by the agedependent manifestation of a number of classical neurodegenerative conditions. To prevent potential damage through leakage of toxic reactive oxygen species from the cellular powerhouses resulting in an age-dependent decline in mitochondrial functions, various quality control mechanisms are in place at the cellular level. One of these mechanisms—dynamic changes in mitochondrial morphology through continuous fission and fusion processes—allows to control the level of mutated mtDNA within cells, keeping thresholds of respiration-deficient mitochondria at bay. In addition, protein turnover pathways as well as degradation of entire damaged or dysfunctional mitochondria represent essential protective mechanisms intimately integrated into cellular physiology. These mechanisms, which have only recently begun to be discovered, are currently the subject of intense research efforts. This is reflected by an impressive increase in the number of respective publications: searching the Web of Knowlegede TM database (Thomson Reuters) for publications using ‘‘mitochondria’’ and ‘‘neurodegeneration’’ as general search terms currently produces more than 1,900 hits, with publication numbers having climbed continuously from less than 75 papers in 2000 to more than 250 yearly publications at present. With dysregulated mitochondrial dynamics having appeared as a new theme in neurodegeneration just a few years ago [1], research on mitochondrial quality control mechanisms has since continued to produce surprising, fundamental new insights into the pathogenesis of certain neurodegenerative disorders. While the interested reader is referred to excellent comprehensive reviews on the general role of mitochondria in neurodegeneration [2], with this mini-cluster of reviews we intend to shed a flashlight on selected, most exciting current developments in the field. S. Frank (&) M. Tolnay Division of Neuropathology, Institute of Pathology, Schonbeinstrasse 40, 4031 Basel, Switzerland e-mail: frankst@uhbs.ch