Mitochondria are highly dynamic organelles which fulfill a plethora of functions. In addition to their prominent role in energy metabolism, mitochondria are intimately involved in various cellular processes, such as the regulation of calcium homeostasis, lipid metabolism, assembly of iron sulfur clusters, stress response and cell death pathways. Therefore it is not surprising that mitochondrial dysfunction has emerged as a key factor in several diseases, including neurodegenerative disorders.
Neurons are critically dependent on mitochondrial function and integrity based on specific morphological, biochemical, and physiological features. Consequently, mitochondrial alterations can promote neuronal dysfunction and degeneration. Mitochondrial dysfunction has long been implicated in the etiopathogenesis of PD, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Our recent studies on the function and dysfunction of PD-associated genes revealed that various aspects of mitochondrial biology appear to be affected, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control. We also observed that common pathological pathways exist in different neurodegenerative diseases that converge on mitochondrial integrity. Therefore, we analyze the regulation of mitochondrial stress response and quality control pathways (Figure 4) and how their dysregulation contributes to specific diseases. In this context we are also addressing the role of interorganellar communication in cellular stress response and signaling pathways.


Figure 4: Mitochondrial stress response pathways. Mitochondria can activate several pathways in response to stress. Accumulation of misfolded proteins within mitochondria induces the mitochondrial unfolded protein response (mtUPR), leading to the transcriptional upregulation of mitochondrial chaperones and proteases. Mitochondrial stress can cause alterations in mitochondrial dynamics. An increase in fusion of mitochondria allows exchange of material and promotes functional complementation. Under more severe stress conditions, mitochondrial fusion is inhibited and ongoing fission leads to fragmentation of the mitochondrial network, which facilitates segregation and elimination of mitochondria by autophagy in a process called mitophagy. When cells are irreversibly damaged in response to drastic or prolonged stress conditions, mitochondria can induce apoptotic cell death by releasing pro-apoptotic factors from the intermembrane space.
©Konstanze Winklhofer