Mechanisms of Mitochondrial Signaling in Neurodegeneration
The brain represents the organ with the highest energy demand and which is, therefore, the organ least adaptable to energy deprivation and to molecular and cellular misconfiguration and dysfunction. Therefore, we investigate mitochondria mainly from the central nervous system with respect to their role in energy metabolism, intra-/intercellular signaling for proper cell function, and survival in health and disease with a focus on the molecular mechanisms that form the basis of pathogenic and protective processes.
We have specialized in investigating the structural-functional characteristics and the regulatory mechanisms of cytochrome c oxidase (COX), the energy converting enzyme which is known to be the most highly regulated mitochondrial respiratory chain complex in mammalian cells. Thus, COX is predestined to play a regulatory role in mitochondrial signaling under physio-/patho-logical conditions. On this note, we have 1) elucidated the COX-mediated mechanism of mitochondrial signaling by allosteric factor (adenine nucleotide and hormone) binding, 2) discovered a hypoxia-induced COX subunit IV isoform switch and the causal correlation of the COX isoform switch with elevated oxidative stress and increased cell vulnerability in a tissue- and brain cell type-specific way, 3) revealed a neurotoxin-mediated COX isoform switch affecting neural cell vulnerability and providing an explanation for brain region- and sex-specificity of neurodegenerative diseases, such as Parkinson's disease, and 4) demonstrated estrogen-mediated mitochondrial neuroprotective mechanisms.
Our primary objectives are 1) the identification and validation of isoform expression patterns and of novel factor binding which modulate COX and could function as potential biomarkers and 2) the investigation of their importance for mitochondrial signaling and neural cell (dys-) function, (mis-) communication, and survival in in vitro and in vivo model systems of mitochondrial and neurodegenerative diseases, such as MELAS and Morbus Parkinson, Morbus Alzheimer. Herewith, we aim at understanding the mechanisms underlying the cause and development of mitochondrial and neurodegenerative diseases. This will build a basis on which diagnostic markers and therapeutic tools can be developed to better cope with these diseases.